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  • 1. Al-Bishri, Awwad
    et al.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Al-Thobaiti, Yasser
    Sunzel, Bo
    Rosenquist, Jan
    Effect of betamethasone on the degree of macrophage recruitment and nerve growth factor receptor p75 immunoreaction during recovery of the sciatic nerve after injury: an experimental study in rats.2008In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 46, no 6, 455-9 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study was designed to explain our previous findings of beneficial effects of betamethasone given perioperatively on decreasing the incidence of neurosensory disturbance after sagittal split osteotomy and improving functional recovery after crush injury to rat sciatic nerves. We analysed the pattern of macrophage recruitment and expression of nerve growth factor p75. MATERIAL AND METHODS: The sciatic nerve was crushed in each of 42 animals by tying the nerve against a glass rod for 30s. Half the rats were given betamethasone and half were not. The effect of betamethasone was evaluated immunohistochemically in a double blind manner after 2, 7 and 17 days using antibodies against macrophage marker (ED1) and p75. RESULTS: We found an initial and significant decrease in the number of macrophages recruited after two days in the group treated with betamethasone compared with controls (p=0.001). By 7 days there were significantly more macrophages in the steroid group than in the control group (p=0.001). There was however, a tendency for the number of p75R to be higher in the in the steroid group but the difference was not significant. At 17 days, there were significantly fewer macrophages in the steroid group (p=0.008) than in the control. CONCLUSION: We conclude that the beneficial effect of a moderate perioperative dose of betamethasone on recovery of a nerve is reflected in the recruitment of macrophages but to only a small extent in expression of p75.

  • 2.
    Alfredson, H.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Öhberg, L.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis?: An investigation using US and colour Doppler, immunohistochemistry, and diagnostic injections2003In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, Vol. 11, no 5, 334-338 p.Article in journal (Refereed)
  • 3.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thorsen, Kim
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Fahlström, Martin
    Umeå University, Faculty of Medicine, Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Johansson, Håkan
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Glutamate NMDAR1 receptors localised to nerves in human Achilles tendons. Implications for treatment?2001In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 9, no 2, 123-126 p.Article in journal (Refereed)
    Abstract [en]

    In this investigation, we show the presence of both free glutamate (microdialysis) and glutamate NMDAR1 receptors (immunohistochemical analyses of tendon biopsies), in tendons from patients with chronic Achilles tendon pain (Achilles tendinosis) and in controls (pain-free tendons). The NMDAR1 immunoreaction was usually confined to acetylcholinesterase-positive structures, implying that the reaction is present in nerves. Glutamate is a potent pain mediator in the human central nervous system, and in animals it has been shown that peripherally administered glutamate NMDA receptor antagonists diminish the response to formalin-induced nociception. Our present finding of glutamate NMDA receptors in human Achilles tendons might have implications for pain treatment.

  • 4.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thorsen, Kim
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper's knee.2001In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 19, no 5, 881-886 p.Article in journal (Refereed)
    Abstract [en]

    This investigation describes, to our knowledge, the first experiment where the microdialysis technique was used to study certain metabolic events in human patellar tendons in combination with immunohistochemical analyses of tendon biopsies. In five patients (four men and one woman) with a long duration (range 12-36 months) of pain symptoms from Jumper's knee (localized tenderness in the patellar tendon verified as tendon changes with ultrasonography or MRI), and in five controls (four men and one woman) with normal patellar tendons, a standard microdialysis catheter was inserted into the patellar tendon under local anestesia. The local concentrations of glutamate (excitatory neurotransmitter) and prostaglandin E2 (PGE2) were registered under resting conditions. Samplings were done every 15 min during a 2 h period. In all individuals (patients and controls) biopsies were taken for immunohistochemical analyses. The results showed that it was possible to detect and measure the concentrations of glutamate and PGE2 in the patellar tendon with the use of microdialysis technique. There were significantly higher concentrations of free glutamate, but not PGE2, in tendons with tendinosis compared to normal tendons. In the biopsies, there were no inflammatory cell infiltrates, but, for the first time, it was shown that there was immunoreaction for the glutamate receptor NMDAR1 in association with nerve structures in human patellar tendons. These findings altogether indicate that glutamate might be involved in painful Jumper's knee, and further emphasizes that there is no chemical inflammation (normal PGE2 levels) in this chronic condition.

  • 5.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bilateral Achilles tendinosis: the similar morphological appearance and the benefit of unilateral treatment has benefits for the contralateral tendon2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, A18-A18 p.Article in journal (Other academic)
  • 6.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unilateral surgical treatment for patients with midportion Achilles tendinopathy may result in bilateral recovery2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 19, 1421-1424 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bilateral midportion Achilles tendinopathy/tendinosis is not unusual, and treatment of both sides is often carried out. Experiments in animals suggest of the potential involvement of central neuronal mechanisms in Achilles tendinosis. OBJECTIVES: To evaluate the outcome of surgery for Achilles tendinopathy. METHODS: This observational study included 13 patients (7 men and 6 women, mean age 53 years) with a long duration (6-120 months) of chronic painful bilateral midportion Achilles tendinopathy. The most painful side at the time for investigation was selected to be operated on first. Treatment was ultrasound-guided and Doppler-guided scraping procedure outside the ventral part of the tendon under local anaesthetic. The patients started walking on the first day after surgery. Follow-ups were conducted and the primary outcome was pain by visual analogue scale. In an additional part of the study, specimens from Achilles and plantaris tendons in three patients with bilateral Achilles tendinosis were examined. RESULTS: Short-term follow-ups showed postoperative improvement on the non-operated side as well as the operated side in 11 of 13 patients. Final follow-up after 37 (mean) months showed significant pain relief and patient satisfaction on both sides for these 11 patients. In 2 of 13 patients operation on the other, initially non-operated side, was instituted due to persisting pain. Morphologically, it was found that there were similar morphological effects, and immunohistochemical patterns of enzyme involved in signal substance production, bilaterally. CONCLUSION: Unilateral treatment with a scraping operation can have benefits contralaterally; the clinical implication is that unilateral surgery may be a logical first treatment in cases of bilateral Achilles tendinopathy.

  • 7.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Willberg, Lotta
    Öhberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ultrasound and doppler-guided artthroscopic shaving for the treatment of patellar tendinopathy/jumper´s knee: biological background and description of method2011In: Anterior knee pain and patellar instability / [ed] Sanchis-Alfonso, Vicente, London: Springer London, 2011, 367-371 p.Chapter in book (Refereed)
    Abstract [en]

    Treatment with ultrasound and Doppler-guided arthroscopic shaving of the region with vessels and nerves outside the dorsal tendon has shown promising clinical results in patients with proximal patellar tendinopathy/Jumper´s knee. The results concerning only a limited patient material has been published in a scientific paper. Results on larger materials are under evaluation for later publication. Proper understanding of the ultrasound and Doppler findings, to enable for a precise and minimal arthroscopic shaving procedure on the dorsal side of the tendon, are cornerstones using this new type of treatment.

  • 8.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Hip Health and Mobility, Vancouver Coastal Health and Research Institute, Vancouver, British Columbia, Canada.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model2011In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 45, no 13, 1017-1022 p.Article in journal (Refereed)
    Abstract [en]

    Background Tenocytes produce substance P (SP) and its receptor (neurokinin-1 receptor (NK-1R) is expressed throughout the tendon tissue, expecially in patients with tendinopathy and tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering the known effects of SP, one might ask whether SP contributes to these canges.

    Objectives To test whether development of tendinosislike changes (hypercellularity and angiogenesis) is accelerated during a 1-week course of ecercise with local administration of SP in an establish Achilles tendinopathy model.

    Methods Rabbits were subjected to a protocol of Achilles tendon overuse for 1 week, in conjunction with SP injections in the paratenon. Exercised control animals received NaCl injections or no injections, and unexercised, uninjected controls were also used. Tenocyte number and vascular density, as well as paratendinous inflammation, were evaluated. Immunohistochemistry and in sity hybridisation to detect NK-1R were conducted.

    Results There was a significant increase in tenocyte number in the SP-injected and NaCl-injected groups compared with both unexercised and exercised, uninjected controls. Tendon blood vessels increased in number in the SP-injected group compared with unexercised controls, a finding not seen in NaCl-injected controls or in uninjected, exercised animals. Paratendinous inflammation was more pronounced in the SP-injected group than in the NaCl controls. NK-1R was detected in blood vessel walls, nerves, inflammatory cells and tenocytes.

    Conclusions SP accelerated the development of tendinosis-like changes in the rabbit. Achilles tendon, which supports theories of a potential role of SP in tendinosis development; a fact of clinical interest since SP effects can be effectively blocked. The angiogenic response to SP injections seems related to parateninitis.

  • 9.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P induces tendinosis-like changes in a rabbit model of Achilles tendon overuseManuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: In previous studies we found evidence favouring that human Achilles tendon cells (tenocytes) are capable of producing the neuropeptide substance P (SP). Furthermore, the preferred receptor for SP (the neurokinin-1 receptor, NK-1 R) was widely expressed throughout the tendon, especially in patients suffering from chronic tendon pain (tendinopathy) with tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering known effects of SP, one might ask whether SP contributes to tendon cell proliferation and neovascularisation in tendinosis. We have an established animal (rabbit) model of Achilles tendinopathy based on overuse in the form of repetitive exercise. Recent studies with this model have shown that tendinosis-like changes are present after 3 weeks of exercise, but not after only 1 week. The current study aimed to test whether the development of tendinosis-like changes would be accelerated during a 1 week course of exercise with repetitive local administration of SP.

    MATERIAL AND METHODS: Four groups of animals (5-6 New Zealand white rabbits per group) were used. Three groups were subjected to the previously established protocol of Achilles tendon overuse for 1 week. One of these groups was given repetitive SP injections in the paratendinous tissue of the Achilles tendon, whereas one group (‘NaCl controls’) was given an equivalent schedule of saline injections. Two additional control groups existed: One in which the animals were neither subjected to the overuse protocol nor to any injections (‘untrained controls’), and one in which the animals trained for 1 week but were not given any injections (‘1 week controls’). Tenocyte number, vascular density, and the possible occurrence of paratendinous inflammation were evaluated. Immunohistochemistry and in situ hybridisation to detect NK-1 R were also conducted.

    RESULTS: There was a significant increase in tenocyte number in the SP-injected group compared to both untrained controls and 1 week controls. However, the same phenomenon was noticed for NaCl controls, i.e. tenocyte number was significantly increased in response to NaCl injections compared to untrained controls. There was an increase in the number of tendon blood vessels in the SP-injected group as compared to untrained controls, and this increase in vascularity was not seen for the NaCl controls or the 1 week controls. Paratendinous inflammation, as evidenced by invasion of inflammatory cells in the paratenon, was clearly more pronounced in the SP-injected group than in the NaCl controls. NK-1 R was detected in blood vessel walls, on nerves, on inflammatory cells, and on tenocytes.

    DISCUSSION AND CONCLUSIONS: The observations suggest that SP induces tenocyte proliferation and angiogenesis in the rabbit Achilles tendon, thus supporting a potential role of this neuropeptide in the processes that occur in tendinosis. The study corroborates findings on the human Achilles tendon in that NK-1 R was expressed on tenocytes and tendon blood vessel walls, thereby providing a potential anatomic basis for the observed effects of SP on the development of tendinosis. The hypercellularity observed in response to NaCl injections might be due increased tissue pressure or to stimulation of endogenous SPproduction, a phenomenon not unheard of. The angiogenic effect of SP injections, on the other hand, appeared to be more specifically related to an induction of inflammation in the paratendon.

  • 10.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Arteries in the area targeted with successful sclerosing injections for Achilles tendinosis are under distinct neural control2006Conference paper (Refereed)
    Abstract [en]

    It has been scientifically demonstrated that there are blood vessels with pathologically high blood flow inside and outside the ventral part of the Achilles tendon in chronic painful tendinosis, but not in pain-free normal Achilles tendons. Injections of local anaesthesia on the outside of the ventral part of the tendon have been found to temporarily abolish the tendon pain, and this has been an inspiration in the development of a new approach in the treatment of tendinosis: Based on ultrasound- (US) and colour Doppler- (CD) guidance, the sclerosing substance polidocanol, for many years used in treatment of varicose veins, was injected targeting the area of high-flow blood vessels just outside the ventral part of the Achilles tendon. The treatment has in pilot studies and a randomized controlled clinical study been shown to cure the pain in about 70-80 % of the patients. Also, follow up examinations, using US and CD, have shown a possible remodeling potential of the tendon. There is some previous information available on the innervation patterns of the human Achilles tendon itself. However, the innervation patterns of the area just outside the ventral part of the tendon, i.e. the area that is targeted by the sclerosing injections (target area), are unknown. This includes a lack of information concerning the nerve-related characteristics of the blood vessels in the area. In this study, therefore, tissue specimens from this target area, obtained during surgical treatment of patients with chronic painful mid-portion Achilles tendinosis, were examined. Histological and immunohistochemical examinations were performed. In the tissue of the target area, in which loose connective tissue and fat cells were frequent constituents, there was a presence of arteries and nerve fascicles. The arteries were of varying dimensions, some being very large. The nerve fascicles were distinguished in sections processed for the pan-neural marker protein gene-product 9.5 (PGP 9.5).  Some of the arteries were supplied by an extensive perivascular innervation, as seen via PGP 9.5 staining. As seen via processing for the rate limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), sympathetic innervation was found to be a constituent of this innervation. There was furthermore a marked occurrence of immunoreactions for the α1-adrenoreceptor in arterial walls. Also, there was a presence of immunoreactions for the substance P (SP)-preferred receptor, the neurokinin-1 (NK-1) receptor in arterial walls. This receptor was particularly detected in the endothelial parts. The study shows that the arteries in the target area are accompanied by nerve fascicles and that there is a presence of a perivascular innervation, as well as a presence of adrenergic and NK-1 receptors in arterial walls, in this region. Thus, arteries in this area are under distinct neural control. The nerve-related characteristics of the area targeted in the successful polidicanol injection treatment for Achilles tendinosis are here for the first time shown.

  • 11.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Nerve-related characteristics of ventral paratendinous tissue in chronic Achilles tendinosis2007In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 15, no 10, 1272-1279 p.Article in journal (Refereed)
    Abstract [en]

    Ultrasound and Doppler examination has shown high blood flow-neovascularisation inside and outside the ventral Achilles tendon in chronic painful tendinosis, but not in pain-free normal Achilles tendons. In patients with Achilles tendinosis, injections with the sclerosing substance polidocanol, targeting the areas with increased blood flow, have been demonstrated to give pain relief. A drawback when interpreting these findings is the fact that the pattern of nerve supply in the target area, i.e. the ventral area of the tendon, is so far unknown. In this study, therefore, tissue specimens from this area, obtained during surgical treatment of patients with chronic painful midportion Achilles tendinosis, were examined. In the examined area, containing loose connective tissue, the general finding was a presence of large and small arteries and nerve fascicles. The nerve fascicles were distinguished in sections processed for the pan-neural marker protein gene-product 9.5. The nerve fascicles contain sensory nerve fibers, as shown via staining for the sensory markers substance P (SP) and calcitonin gene-related peptide, and sympathetic nerve fibers as seen via processing for tyrosine hydroxylase. In addition, there were immunoreactions for the SP-preferred receptor, the neurokinin-1 receptor, in blood vessel walls and nerve fascicles. Some of the blood vessels were supplied by an extensive peri-vascular innervation, sympathetic nerve fibers being a distinct component of this innervation. There was also a marked occurrence of immunoreactions for the alpha1-adrenoreceptor in arterial walls as well as in the nerve fascicles. Altogether, these findings suggest that the area investigated is under marked influence by the nervous system, including sympathetic and sensory components. Thus, sympathetic/sensory influences may be involved in the pain mechanisms from this area. In conclusion, the nerve-related characteristics of the area targeted by the polidicanol injection treatment for Achilles tendinosis, are shown here for the first time.

  • 12.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 150, no 1-3, 81-87 p.Article in journal (Refereed)
    Abstract [en]

    Nerve signal substances, such as the tachykinin substance P (SP), may be involved in the changes that occur in response to tendinopathy (tendinosis). It is previously known that the level of SP innervation within tendon tissue is limited, but results of experimental studies have suggested that SP may have stimulatory, angiogenetic and healing effects in injured tendons. Therefore, it would be of interest to know if there is a local SP-supply in tendon tissue. In the present study, the patterns of expression of SP and its preferred receptor, the neurokinin-1 receptor (NK-1 R), in normal and tendinosis human Achilles tendons were analyzed by use of both immunohistochemistry and in situ hybridization. We found that there was expression of SP mRNA in tenocytes, and that tenocytes showed expression of NK-1 R at protein as well as mRNA levels. The observations concerning both SP and NK-1 R were most evident for tenocytes in tendinosis tendons. Our findings suggest that SP is produced in tendinosis tendons, and furthermore that SP has marked effects on the tenocytes via the NK-1 R. It cannot be excluded that the SP effects are of importance concerning the processes of reorganization and healing that occur for tendon tissue in tendinosis. In conclusion, it appears as if SPergic autocrine/paracrine effects occur in tendon tissue during the processes of tendinosis, hitherto unknown effects for human tendons.

  • 13.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    University of British Columbia, Vancouver, Vancouver Coastal Health and Research Institute.
    Gaida, James Edmund
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Stjernfeldt, Johanna Elgestad
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Backman, Clas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Tenocyte hypercellularity and vascular proliferation in a rabbit model of tendinopathy: contralateral effects suggest the involvement of central neuronal mechanisms2011In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 45, no 5, 399-406 p.Article in journal (Refereed)
    Abstract [en]

    Objective To determine whether there are objective findings of tendinosis in a rabbit tendinopathy model on exercised and contralateral (non-exercised) Achilles tendons. Design Four groups of six New Zealand white rabbits per group were used. The animals of one (control) group were not subjected to exercise/stimulation. Interventions Animals were subjected to a protocol of electrical stimulation and passive flexion-extension of the right triceps surae muscle every second day for 1, 3 or 6 weeks. Main Outcome Measures Tenocyte number and vascular density were calculated. Morphological evaluations were also performed as well as in-situ hybridisation for vascular endothelial growth factor (VEGF) messenger RNA. Results There was a significant increase in the tenocyte number after 3 and 6 weeks of exercise, but not after 1 week, in comparison with the control group. This was seen in the Achilles tendons of both legs in experimental animals, including the unexercised limb. The pattern of vascularity showed an increase in the number of tendon blood vessels in rabbits that had exercised for 3 weeks or more, compared with those who had exercised for 1 week or not at all. VEGF-mRNA was detected in the investigated tissue, with the reactions being more clearly detected in the tendon tissue with tendinosis-like changes (6-week rabbits) than in the normal tendon tissue (control rabbits). Conclusions There were bilateral tendinosis-like changes in the Achilles tendons of rabbits in the current model after 3 weeks of training, suggesting that central neuronal mechanisms may be involved and that the contralateral side is not appropriate as a control.

  • 14.
    Backman, Ludvig
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wennstig, Gabriel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Endogenous substance P production in the Achilles tendon increases with loading in an in vivo model of tendinopathy: peptidergic elevation preceding tendinosis-like tissue changes2011In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 11, no 2, 133-140 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: To quantify the intratendinous levels of substance P (SP) at different stages of overload in an established modelfor Achilles tendinopathy (rabbit). Also, to study the distribution of the SP-receptor, the NK-1R, and the source of SP, in thetendon. 

    Methods: Animals were subjected to the overuse protocol for 1, 3 or 6 weeks. One additional group served as unexercisedcontrols. Immunoassay (EIA), immunohistochemistry (IHC), and in situ hybridisation (ISH) were performed.

    Results: EIA revealedincreased SP-levels in the Achilles tendon of the exercised limb in all the experimental groups as compared to in thecontrols (statistically significant; p=0.01). A similar trend in the unexercised Achilles tendon was observed but was not statisticallysignificant (p=0.14). IHC and in ISH illustrated reactions of both SP and NK-1R mainly in blood vessel walls, but the receptorwas also found on tenocytes.

    Conclusions: Achilles tendon SP-levels are elevated already after 1 week of loading. This showsthat increased SP-production precedes tendinosis, as tendinosis-like changes occur only after a minimum of 3 weeks of exercise,as shown in a recent study using this model. We propose that central neuronal mechanism may be involved as similar trends wereobserved in the contralateral Achilles tendon.

  • 15.
    Bagge, J.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Nerve ingrowth into tendon tissue in Achilles tendinosis: a Case Report2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, A8-A8 p.Article in journal (Other academic)
  • 16.
    Bagge, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    In situ hybridization studies favouring the occurrence of a local production of BDNF in the human Achilles tendon2012In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 27, no 9, 1239-1246 p.Article in journal (Refereed)
    Abstract [en]

    Brain derived neurotrophic factor (BDNF) is a multipotent neurotrophin known for its growth-influencing and apoptosis-modulating functions, as well as for its function to interact with neurotransmitters/neuromodulators. BDNF is reported to be mainly produced in the brain. BDNF can be absorbed into peripheral tissue from the blood stream. Expression of this neurotrophin at the protein level, as well as of the neurotrophin receptor p75, has been previously shown for the principal cells (tenocytes) of the Achilles tendon. However, there is no proof at the mRNA level that BDNF is produced by the tenocytes. As the Achilles tendon tenocytes show "neuronal-like" characteristics, in the form of expressions favouring synthesis of several neuromodulators/neurotransmitters, and as BDNF especially is produced in neurons, it is of interest to confirm this. In the present study, therefore, in situ hybridization for demonstration of BDNF mRNA was performed on biopsies from Achilles tendons of patients with tendinosis and pain-free non-tendinosis individuals. The results showed that the tenocytes of both groups exhibited BDNF mRNA reactions. These observations indeed favour the idea that BDNF is produced by tenocytes in the human Achilles tendon, why Achilles tendon tissue is a tissue in which BDNF can be locally produced. BDNF can have modulatory functions for the tenocytes, including apoptosis-modifying effects via actions on the p75 receptor and interactive effects with neurotransmitters/neuromodulators produced in these cells. This possibility should be further studied for Achilles tendon tissue.

  • 17.
    Bagge, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Gaida, JE
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Physical activity level in Achilles tendinosis is associated with blood levels of pain-related factors: a pilot study2011In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 21, no 6, E430-E438 p.Article in journal (Refereed)
    Abstract [en]

    Physical activity affects the pain symptoms for Achilles tendinosis patients. Brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-alpha) and their receptors have been detected in human Achilles tendon. This pilot study aimed to compare serum BDNF and soluble tumor necrosis factor receptor I (sTNFRI) levels in Achilles tendinosis patients and healthy controls and to examine the influence of physical activity, and BMI and gender, on these levels. Physical activity was measured with a validated questionnaire, total physical activity being the parameter analyzed. Physical activity was strongly correlated with BDNF among tendinosis women [Spearman's rho (rho) = 0.90, P < 0.01] but not among control women (rho = -0.08, P = 0.83), or among tendinosis and control men. Physical activity was significantly correlated with sTNFRI in the entire tendinosis group and among tendinosis men (rho = 0.65, P = 0.01), but not in the entire control group or among control men (rho = 0.04, P = 0.91). Thus, the physical activity pattern is related to the TNF and BDNF systems for tendinosis patients but not controls, the relationship being gender dependent. This is new information concerning the relationship between physical activity and Achilles tendinosis, which may be related to pain for the patients. This aspect should be further evaluated using larger patient materials.

  • 18.
    Bagge, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unexpected presence of the neurotrophins NGF and BDNF and the neurotrophin receptor p75 in the tendon cells of the human Achilles tendon2009In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 24, no 7, 839-848 p.Article in journal (Refereed)
    Abstract [en]

    Neurotrophins are substances that have been shown to be important in growth and remodelling phases in different types of tissue. There is no information concerning the possible occurrences of neurotrophins and their receptors in tendons. In this study, sections of both chronic painful (tendinosis) and pain-free (non-tendinosis) human Achilles tendons were immunohistochemically stained with antibodies against the neurotrophins NGF and BDNF, and their receptors TrkA, TrkB and p75. There were marked immunoreactions for NGF and BDNF in the tendon cells (tenocytes) of both tendinosis and non-tendinosis specimens. The tenocytes were also reactive for the receptor p75, but not for the receptors TrkA and TrkB. In addition, p75 immunoreactions were seen in nerve fascicles and in the walls of arterioles. This is the first study to identify neurotrophins in the tenocytes of human tendon. It is clear from this study that the local cells of tendons are sources of neurotrophins. The neurotrophins may play an important role in the tendon through their interaction with the receptor p75 in the tenocytes. These interactions may regulate tropic modulatory, and apoptotic effects. In conclusion, the observations show a new concept concerning production and function of neurotrophins, namely in the tenocytes of tendons.

  • 19.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of the neuropeptide Y 1 receptor in tenocytes and blood vessel walls in the human Achilles tendon2009In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 43, no 13, 1136-1142 p.Article in journal (Refereed)
    Abstract [en]

    Background: There are still questions concerning the mechanisms of development of chronic pain and impaired function of tendons (tendinosis). Aspects that are known to occur are cell proliferation, angiogenesis and altered blood flow regulation. Neuropeptide NPY (NPY) is widely distributed in the body and has powerful effects in relation to these processes. NPY has its effects via the G-protein-coupled Y receptors. There is no information concerning the presence or absence of NPY receptors in Achilles tendons or other tendons.

    Objective: To clarify the expression patterns of the NPY receptors Y1 and Y2 in normal and tendinosis Achilles tendons of man.

    Methods: Immunohistochemical methods were used. Examination on NPY was carried out in parallel.

    Results: The tenocytes showed strong immunoreactions for the Y1 receptor. The immunoreactions were more intense in the tenocytes of the tendinosis tendons than in those of the non-tendinosis tendons. The rounded/oval tenocytes typically seen in tendinosis tendons exhibited marked Y1 receptor reactions on their exterior. Pronounced Y1 reactions were seen in the smooth muscle of the arterioles of both tendinosis and non-tendinosis tendons. No reactions for the Y2 receptor were noted. NPY was detected in nerve fascicles and in the perivascular innervation.

    Conclusions: The present study shows that there is a morphologic correlate for the occurrence of pronounced NPY effects via the Y1 receptor in both tenocytes, this especially being a fact for tendinosis tendons, and blood vessel walls in the Achilles tendon. The findings are of particular interest as NPY is known to have proliferative, angiogenic and blood vessel regulating effects. The effects of targeting the Y1 receptor in tendinosis is an interesting task to be further evaluated.

  • 20.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The innervation pattern of the human Achilles tendon: studies of the normal and tendinosis tendon with markers for general and sensory innervation2005In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 320, no 1, 201-206 p.Article in journal (Refereed)
    Abstract [en]

    Pain-free normal Achilles tendons and chronic painful Achilles tendons were examined by the use of antibodies against a general nerve marker (protein gene-product 9.5, PGP9.5), sensory markers (substance P, SP; calcitonin gene-related peptide, CGRP), and immunohistochemistry. In the normal tendons, immunoreactions against PGP9.5 and against SP/CGRP were encountered in the paratendinous loose connective tissue, being confined to nerve fascicles and to nerve fibers located in the vicinity of blood vessels. To some extent, these immunoreactions also occurred in the tendon tissue proper. Immunoreaction against PGP9.5 and against SP/CGRP was also observed in the tendinosis samples and included immunoreactive nerve fibers that were intimately associated with small blood vessels. In conclusion, Mechanoreceptors (sensory corpuscles) were occasionally observed, nerve-related components are present in association with blood vessels in both the normal and the tendinosis tendon.

  • 21.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Immunohistochemical and in situ hybridization observations favor a local catecholamine production in the human Achilles tendon2008In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 23, no 2, 197-208 p.Article in journal (Refereed)
    Abstract [en]

    Results of recent studies using immunohistochemistry show evidence of an occurrence of catecholamine production in the cells (tenocytes) of patellar tendons exhibiting tendinopathy (tendinosis). In the present study, antibodies against the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) and alpha1-adrenoreceptors were applied to sections of specimens of normal and tendinosis Achilles tendons. In situ hybridization using a probe detecting human TH mRNA was also utilized. It was found that sympathetic innervation was very scarce. On the other hand, there were distinct alpha1-adrenoreceptor immunoreactions in blood vessel walls. Interestingly, tenocytes, particularly from tendinosis samples in which the tenocytes showed an abnormal shape (not the typical slender appearance), displayed TH immunoreactions and reactions for TH mRNA. Of further interest was the finding of alpha1-adrenoreceptor immunoreactions in tenocytes. The observations show not only evidence of local catecholamine production at the protein level, which was the case in recent studies for the patellar tendon, but also at the mRNA level. The observations suggest that the tenocytes, especially those with disfigured appearances in tendinosis, can produce catecholamines and also that they can respond to sympathetic transmitters. This is of interest as adrenergic stimulation in other parts of the body is known to induce degenerative/apoptotic and proliferative events, features which are seen in Achilles tendinosis. These observations are completely new findings concerning the human Achilles tendon. It is likely that locally produced catecholamines and the occurrence of autocrine/paracrine effects of these substances are of great relevance during the process of tendinosis.

  • 22.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Observations in favor of a presence of local catecholamine production in the human Achilles tendon - of importance when understanding potential adrenergic effects in Achilles tendinosis.2006Conference paper (Refereed)
    Abstract [en]

    The mid-portion of the Achilles tendon is a frequently injured and pathologically affected tendon region. Achilles tendinosis presents with chronic tendon pain and impaired function, and most often occurs in the mid-portion of the tendon. Nerve-related effects are likely to be of great significance in the pathogenesis of this condition, and information on innervation patterns is therefore of importance. However, the available information on these aspects is limited for the human Achilles tendon. Via staining for a general nerve marker it has previously been shown that there is a presence of innervation in the loose paratendinous connective tissue and to some extent also within the tendon tissue proper. This innervation has been found to partly conform to sensory innervation. There is no information at all on the patterns of sympathetic innervation in the human Achilles tendon. This is a drawback as it is crucial to know the basis for adrenergic effects on blood vessel regulation in tendinosis and as efferent sympathetic nerve activities may be related to pain symptoms. In the present study, therefore, specimens of tendon tissue from the human Achilles tendon of both tendinosis patients and normal controls were immunohistochemically examined concerning expression of the rate limiting enzyme in catecholamine production, tyrosine hydroxylase (TH), and of neuropeptide Y (NPY). In normal tendons, TH- and NPY-immunoreactive nerve fibers were occasionally detected in nerve fascicles and in arterial walls in the paratendinous tissue, but were not detected with certainty within the tendon tissue proper. In the specimens of tendinosis affected tendons, TH-and NPY-immunoreactive nerve fibers were almost non-existent. Surprisingly, however, TH-immunoreactions could be seen in the tendon cells (tenocytes) themselves. Sections were also processed for demonstration of α1-, α2a-, and β1- adrenoreceptors. It was hereby seen that there were immunoreactions for adrenergic receptors in the walls of some of the blood vessels, as well as in some of the tenocytes. The observations show that there is a limited sympathetic innervation at the level of the paratendinous tissue and in principle a non-existent such innervation within the tendon tissue proper. On the other hand, as evidenced by findings of TH-immunoreaction in tenocytes, it appears as if there is a local production of catecholamines within the tendon tissue proper itself. Thus, the tenocytes might be an important source of mediators that bind to the adrenergic receptors in the tissue. The observations of adrenergic receptors on tenocytes are furthermore of interest as adrenergic stimulation in other situations can lead to degenerative/apoptotic events and an affection on cell growth. These facts are thus highly interesting when trying to understand how such events can occur in Achilles tendinosis. Similarly, cartilage and menisci have in recent studies been found to harbor cells that express adrenergic receptors, but nevertheless to be very scarcely equipped with nerves. Although there is a very limited sympathetic innervation in the Achilles tendon, our observations show that there is a morphologic correlate for the occurrence of adrenergic actions in the tendon, via effects of locally produced catecholamines.

  • 23.
    Bjur, Dennis
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Presence of a non-neuronal cholinergic system and occurrence of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance regarding Achilles tendon tendinosis (tendinopathy)2008In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 331, no 2, 385-400 p.Article in journal (Refereed)
    Abstract [en]

    Limited information is available concerning the existence of a cholinergic system in the human Achilles tendon. We have studied pain-free normal Achilles tendons and chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2) muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M(2)R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M(2)R immunoreactivity was present in the endothelium. M(2)R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M(2)R immunoreactivity was highly variable, tendinosis tendons that exhibit hypercellularity and hypervascularity showing the highest levels of immunostaining. Immunoreaction for ChAT and VAChT was detected in tenocytes in tendinosis specimens, particularly in aberrant cells. In situ hybridization revealed that mRNA for ChAT is present in tenocytes in tendinosis specimens. Our results suggest that autocrine/paracrine effects occur concerning the tenocytes in tendinosis. Up-regulation/down-regulation in the levels of M(2)R immunoreactivity possibly take place in tenocytes and blood vessel cells during the various stages of tendinosis. The presumed local production of acetylcholine (ACh), as evidenced by immunoreactivity for ChAT and VAChT and the detection of ChAT mRNA, appears to evolve in response to tendinosis. These observations are of importance because of the well-known vasoactive, trophic, and pain-modulating effects that ACh is known to have and do unexpectedly establish the presence of a non-neuronal cholinergic system in the Achilles tendon.

  • 24.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Increased expression of cannabinoid CB(1) receptors in achilles tendinosis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, e24731- p.Article in journal (Refereed)
    Abstract [en]

    Background: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB(1)) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis.

    Methodology: Cannabinoid CB(1) receptor immunoreactivity (CB(1)IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons.

    Principal Findings: CB(1)IR was seen as a granular pattern in the tenocytes. CB(1)IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB(1) receptor expression in tendinosis tissue compared to control tissue.

    Conclusion: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder.

  • 25.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Distribution of general (PGP 9.5) and sensory (substance P/CGRP) innervations in the human patellar tendon.2006In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 14, no 2, 125-132 p.Article in journal (Refereed)
    Abstract [en]

    There is no information on the pattern of blood vessel innervation, and in principle no information on innervation in general, in the human patellar tendon. In the present study, biopsies from the proximal part of normal and pain-free patellar tendons (11 men, mean age 33 years) were examined. The specimens were evaluated by using antibodies against the general nerve marker protein gene-product 9.5 (PGP 9.5) and the sensory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), and immunohistochemistry. It was observed that the arteries, and to some extent the small vessels, in the loose paratendinous connective tissue were supplied with PGP 9.5- as well as SP- and CGRP-innervations. There was a marked PGP 9.5-like immunoreaction (LI), and to some extent also SP- and CGRP-LI, in the large nerve fascicles in this tissue. In the tendon tissue proper, PGP 9.5-LI was detected in nerve fibers located in the vicinity of some of the blood vessels and in thin nerve fascicles. There was a low degree of SP- and CGRP-innervation in the tendon tissue proper. The observations give a morphologic correlate for the occurrence of nerve-mediated effects in the patellar tendon. Particularly it seems as if there is a marked nerve-mediated regulation of the blood vessels supplying the tendon, at the level where they course in the loose paratendinous connective tissue.

  • 26.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Extensive expression of markers for acetylcholine synthesis and of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendonosis - a case study2006Conference paper (Refereed)
    Abstract [en]

    We have recently, in a study of a group of patients with chronic painful patellar tendon tendinosis (“jumper’s knee”), obtained evidence favoring the occurrence of an upregulation of a non-neuronal cholinergic system in this condition. Today, there is a new line of treatment of patellar tendinosis in the form of doppler guided sclerosing injections (Polidokanol), a treatment that has turned out to be very successful. However, the mechanisms for this therapy remain somewhat unclear. After an average of three treatments, a majority of the patients experience a significant decrease of pain symptoms. Nevertheless, a few patients seem resistant to this therapy, exhibiting no clear decrease in pain sensation.

    Therefore, we have in this pilot study investigated biopsies from the patellar tendon of one such therapy-resistant patient (male, exhibiting long duration of pain symptoms and showing radiological findings confirming tendinosis), using immunohistochemical methods examining both chemically fixed and unfixed tissue. The results were compared with our previous findings of both normal and tendinosis tendons.

    Morphologically, there was hypercellularity in the tendon tissue. The immunohistochemical studies showed that there were marked immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) (fixed tissue), as well as for the M2 muscarinic acetylcholine receptor (unfixed tissue), in the overwhelming majority of the tenocytes. The levels of immunoreactions were more pronounced than those obtained in the tendinosis tissue of the previously studied patients and clearly more pronounced than those of tendon tissue of controls.

    In conclusion, our theory is that cases of severe tendinosis, exhibiting therapy-resistance, are related to the occurrence of an excessive local acetylcholine (ACh) production that appears to be even more prominent than in tendinosis in general. This case study emphasizes the need for further investigation regarding the role of non-neuronal ACh in therapy-resistant patellar tendon tendinosis.

  • 27.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Findings favoring production of non-neuronal acetylcholine with possible autocrine/paracrine effects in chronic painful patellar tendon tendinosis.2006Conference paper (Refereed)
    Abstract [en]

    The innervation pattern of the human patellar tendon is largely unknown. That includes the situation for patients suffering from patellar tendon tendinosis (“jumper’s knee”). Concerning the possible occurrence of a cholinergic system in the human patellar tendon, very little information is available.

    In the present study, specimens of pain-free normal (n=16) and chronically painful tendinosis (n=7) tendons were examined by different immunohistochemical and histochemical methods.

    It was found that parts of the tenocytes of the tendinosis tendons displayed immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT). Furthermore, immunoreactions for the M2 muscarinic acetylcholine receptor could be detected in both blood vessel cells and tenocytes, especially in tendinosis specimens. Acetylcholinesterase activity was shown for scarce nerve fibers associated with small blood vessels in both the normal and the tendinosis tendons.

    The observations suggest that, besides the occurrence of a scanty nerve related cholinergic system in the human patellar tendon, there is a local non-neuronal cholinergic system as well, at least in tendinosis tendons. As ChAT and VAChT were detected in tenocytes of these tendons, such tenocytes are likely to produce acetylcholine (ACh) locally, and as both tenocytes and blood vessel cells were found to express the M2 receptor, it is likely that both of these cell types may be influenced by ACh.

    Thus, in conclusion, there appears to be an upregulation of the cholinergic system, and an occurrence of autocrine/paracrine effects in this system, in the tendinosis patellar tendon. This observation is of importance, not only related to the fact that tendinosis patients exhibit marked pain, but also as stimulation of ACh receptors can lead to cell proliferation, effects on collagen accumulation and angiogenesis, all of which are phenomena that occur in tendinosis.

  • 28.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Idrottsmedicin.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Immunohistochemical and histochemical findings favoring the occurrence of autocrine/paracrine as well as nerve-related cholinergic effects in chronic painful patellar tendon tendinosis.2006In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 69, no 10, 808-819 p.Article in journal (Refereed)
    Abstract [en]

    The pathogenesis of the pain in patellar tendon tendinosis ("jumper's knee") is unclear. We have recently presented new information about the sensory nervous system in the human patellar tendon, but there is very little information regarding the possible occurrence of a cholinergic system in this tendon. In the present study, specimens of pain-free normal tendons and chronically painful tendinosis tendons were examined by different immunohistochemical and histochemical methods. Antibodies against the M(2) receptor, choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT) were applied, and staining for demonstration of activity of acetylcholinesterase (AChE) was also utilized. It was found that immunoreactions for the M(2) receptor could be detected intracellularly in both blood vessel cells and tenocytes, especially in tendinosis specimens. Furthermore, in the tendinosis specimens, some tenocytes were seen to exhibit immunoreaction for ChAT and VAChT. AChE reactions were seen in fine nerve fibers associated with small blood vessels in both the normal control tendons and the tendinosis tendons. The observations suggest that there is both a nerve related and a local cholinergic system in the human patellar tendon. As ChAT and VAChT immunoreactions were detected in tenocytes of tendinosis tendons, these cells might be a source of local acetylcholine (Ach) production. As both tenocytes and blood vessel cells were found to exhibit immunoreactions for the M(2) receptor, it is likely that both of these tissue cells may be influenced by ACh. Thus, in conclusion, there appears to be an upregulation of the cholinergic system, and an occurrence of autocrine/paracrine effects in this system, in the tendinosis patellar tendon.

  • 29.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    In situ hybridization studies confirming recent findings of the existence of a local nonneuronal catecholamine production in human patellar tendinosis.2007In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 70, no 10, 908-911 p.Article in journal (Other academic)
    Abstract [en]

    We have in recent studies presented unexpected immunohistochemical evidence favoring the existence of a local production of catecholamines, and an occurrence of adrenergic receptors on the tendon cells (tenocytes), in the human patellar tendon. This was particularly noticed for tendons from patients suffering from tendinosis (chronic tendon pain), which has led us to propose an involvement of this autocrine/paracrine system in the development of tendinosis, especially since catecholamines have been reported to be modulators of tissue remodeling and pain processes. However, the findings concerning catecholamine production have so far only been noted at the level of protein detection, and for this reason, the aim of the present study was to confirm the previous immunohistochemical results by using in situ hybridization (ISH) technique. A ssDNA probe detecting human mRNA for the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) was applied. The ISH results revealed that there were clear reactions indicating the existence of mRNA for TH in tenocytes of tendinosis specimens. It was generally noted that disfigured tenocytes were the ones with the most distinct reactions, while normally looking tenocytes hardly displayed any reactions at all. In conclusion, this study presents the first evidence at the mRNA level of the existence of a local nonneuronal production of catecholamines in human patellar tendon tissue. The findings add to recent observations of the occurrence of a local production in tendons of signal substances traditionally related to neurons.

    (c) 2007 Wiley-Liss, Inc.

  • 30.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Marked occurrence of receptors for sympathetic and cholinergic transmitters and for substance P in the blood vessels of the human patellar tendon.2005Conference paper (Refereed)
    Abstract [en]

    INTRODUCTION: Human tendons have generally been considered to be hyponeural. However, in our recent studies of the patellar tendon in both healthy individuals and patients with tendinosis (jumper’s knee), we have noted the presence of general (PGP 9.5) and sensory (substance P [SP]) innervations, especially in the loose paratendinous connective tissue. Furthermore, we have observed a pronounced expression of the neurokinin-1 receptor (the preferred receptor for SP) in blood vessel walls. The findings are of interest as a new successful treatment of tendinosis has emerged in form of doppler guided sclerosing injections (substance: Polidokanol), targeting areas with neovascularisation, and as SP is known to be of importance when neurogenic angiogenesis participates in diseases. AIM: To further investigate the blood vessels of the normal and tendinosis-affected human patellar tendon regarding autonomic innervation. METHODS: Immunohistochemistry and histochemistry, including antibodies against the sympathetic nerve markers tyroxine hydroxylase and neuropeptide Y and against various adrenoreceptors (α1, α2a, β1), as well as stainings for substances related to cholinergic functions such as the muscarinic M2 receptor, acetylcholinesterase and vesicular acetylcholine transporter. RESULTS/CONCLUSIONS: The preliminary results so far, indicate that there is indeed an occurrence of both sympathetic and cholinergic innervations in the tendon, not the least shown via the presence of sympathetic and cholinergic receptors in blood vessel walls; a fact that further supports the theories that blood vessel regulation via neurotransmitters/-modulators might be a key factor in the pathological mechanisms of jumper’s knee.

  • 31.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man.2007In: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 70, no 4, 310-324 p.Article in journal (Refereed)
    Abstract [en]

    Changes in the patterns of production and in the effects of signal substances may be involved in the development of tendinosis, a chronic condition of pain in human tendons. There is no previous information concerning the patterns of sympathetic innervation in the human patellar tendon. In this study, biopsies of normal and tendinosis patellar tendons were investigated with immunohistochemical methods, including the use of antibodies against tyrosine hydroxylase (TH) and neuropeptide Y, and against alpha(1)-, alpha(2A)-, and beta(1)-adrenoreceptors. It was noticed that most of the sympathetic innervation was detected in the walls of the blood vessels entering the tendon through the paratendinous tissue, and that the tendon tissue proper of the normal and tendinosis tendons was very scarcely innervated. Immunoreactions for adrenergic receptors were noticed in nerve fascicles containing both sensory and sympathetic nerve fibers. High levels of these receptors were also detected in the blood vessel walls; alpha(1)-adrenoreceptor immunoreactions being clearly more pronounced in the tendinosis tendons than in the tendons of controls. Interestingly, immunoreactions for adrenergic receptors and TH were noted for the tendon cells (tenocytes), especially in tendinosis tendons. The findings give a morphological correlate for the occurrence of sympathetically mediated effects in the patellar tendon and autocrine/paracrine catecholamine mechanisms for the tenocytes, particularly, in tendinosis. The observation of adrenergic receptors on tenocytes is interesting, as stimulation of these receptors can lead to cell proliferation, degeneration, and apoptosis, events which are all known to occur in tendinosis. Furthermore, the results imply that a possible source of catecholamine production might be the tenocytes themselves. Microsc. Res. Tech., 2007. (c) 2007 Wiley-Liss, Inc.

  • 32.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Extensive expression of markers for acetylcholine synthesis and of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendinosis - a pilot study.2007In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 80, no 24-25, 2235-2238 p.Article in journal (Refereed)
    Abstract [en]

    We have recently obtained evidence favoring the occurrence of an up-regulation of a non-neuronal cholinergic system in chronic painful patellar tendon tendinosis. It seems possible that this up-regulation to a certain degree may be involved in the manifestations of the disease. Today, there is a new, very successful, line of treatment of patellar tendinosis in the form of Doppler guided sclerosing injections. However, a few patients seem resistant to this therapy. Therefore, we have in this pilot study investigated biopsies from the patellar tendon of three such therapy-resistant patients, using immunohistochemistry. In situ hybridization was also applied. Comparisons were made with a material of specimens from both normal (n=16) and tendinosis (n=7) tendons, also previously examined. The study showed that there were extensive immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter, as well as for the M(2) muscarinic acetylcholine receptor, in the overwhelming majority of the tenocytes. The immunoreactions were more pronounced than those generally obtained in the tendinosis tissue of the previously studied patients and clearly more pronounced than those of patellar tendon tissue of controls. Also, for the first time, we here present findings of mRNA for ChAT within tenocytes. In conclusion, it appears as if there is an excessive local acetylcholine (ACh) production and an occurrence of marked ACh effects in cases of severe tendinosis. An excessive production of local ACh might be related to pain sensation and the processes that occur in tendinosis development, such as cell proliferation. Thus, the results of this pilot study suggest that non-neuronal ACh is highly involved in the pathology of therapy-resistant patellar tendinosis.

  • 33.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Marked sympathetic component in the perivascular innervation of the dorsal paratendinous tissue of the patellar tendon in arthroscopically treated tendinosis patients.2008In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 16, no 6, 621-6 p.Article in journal (Refereed)
    Abstract [en]

    During the recent years, a few studies have shed new light on the innervation patterns of the human patellar tendon, but the area of the loose paratendinous connective tissue dorsal to the proximal tendon proper has yet not been investigated. That is a drawback, since this is the area targeted in promising treatment regimens of chronic painful patellar tendinosis, namely sclerosing Polidocanol injection therapy, and a new surgical method conforming to ultrasound and color Doppler guided arthroscopic shaving, directed at neovessels found in the region. The present study thus aimed at investigating the paratendinous area dorsal to the proximal patellar tendon proper in seven patients being operated for tendinosis. Biopsies were collected through the new arthroscopic technique, approaching the tendon from the dorsal side. Samples were investigated using immunohistochemistry with antibodies delineating general (PGP 9.5), sensory (SP/CGRP), and sympathetic (TH/NPY) nerve patterns, and also antibodies against alpha1- and alpha2A-adrenoreceptors. Both small and large blood vessels had a marked perivascular innervation (PGP 9.5). Surprisingly, this perivascular innervation was found only to a very limited extent to correspond to sensory nerves, while there were marked immunoreactions for sympathetic markers. Adrenoreceptor immunoreactions frequently occurred in blood vessel walls. In conclusion, this study demonstrates, for the first time, the innervation patterns of the area dorsal to the patellar tendon in man. It shows that the area investigated is under marked influence by the sympathetic nervous system. Thus, sympathetic effects are likely to occur for blood vessels of the area, which is interesting since color Doppler has revealed that vessels of this area ("neovessels") display a pathologically high blood flow in tendinosis. The findings are discussed in relation to aspects of vascular regulation, and to pain symptoms of tendinosis.

  • 34.
    Danielson, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Andersson, Gustav
    Alfredson, Håkan
    Forsgren, Sture
    Marked sympathetic component in the perivascular innervation of the dorsal paratendinous tissue targeted in sclerosing Polidocanol injection therapy of patellar tendinosisManuscript (Other academic)
  • 35.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Differentiation of heart Purkinje fibres: an immuno- and enzyme histochemical and ultrastructural study1982Doctoral thesis, comprehensive summary (Other academic)
  • 36.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    New data favouring that neurotrophins are of importance in arthritis2009In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, no 4, 122- p.Article in journal (Other academic)
    Abstract [en]

    Neurotrophins are important in inflammation. In an article in Arthritis Research & Therapy, Barthel and collaborators give new information on the existence of neurotrophin production in the synovial tissue of arthritic joints. These findings, together with other recent findings, stress that neurotrophins should be considered important factors in arthritis. This is reinforced by the facts that they are also produced by articular chondrocytes and that receptors for these are present in the synovial tissue and on chondrocytes. The importance of neurotrophins in joints should be further studied, including examinations on the efficacy of interfering with their effects in arthritis.

  • 37.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of ChAT mRNA and a very marked alpha 7nAChR immunoreaction in the synovial lining layer of the knee joint2012In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 91, no 21-22, 1043-1047 p.Article in journal (Refereed)
    Abstract [en]

    Aims: The aim was to examine if there is evidence of acetylcholine (ACh) production within the synovial lining layer and to examine the pattern of alpha 7nAChR expression in the layer. This layer is of relevance clinically as it becomes thickened in response to both rheumatoid arthritis (RA) and osteoarthritis (OA) and as it has been shown to produce proteases that are involved in the cartilage destruction. Main methods: Synovial tissue specimens from the knee joint of patients with RA and OA undergoing prosthetic surgery were examined. In situ hybridization and immunohistochemistry were used for the evaluation of ChAT reaction patterns. Immunohistochemistry was utilized for demonstration of activity of alpha 7nAChR. Key findings: There were ChAT mRNA reactions in the synovial lining layer of both patient categories. On the other hand, no ChAT immunoreactions were detected in the layer. There was a very marked alpha 7nAChR immunoreaction. Significance: There is a potential for ACh production within the synovial lining layer as there are ChAT mRNA reactions. However, the level of ACh production is apparently very low. It is thus possible that there is a down-regulation of ACh production but an apparent upregulation in expression level of alpha 7nAChR. Based on the knowledge that the non-neuronal cholinergic system can have anti-inflammatory effects, the low level of ACh production in the synovial lining layer can be a drawback for the arthritic joints. (C) 2012 Elsevier Inc. All rights reserved.

  • 38.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Recent studies using an overuse animal model show that signal substances are highly involved in muscle derangement and muscle inflammation2013In: Proceedings of the International Congress on Sports Science Research and Technology Support / [ed] Jan Cabri, Pedro Pezarat Correia, João Barreiros, SciTePress, 2013, Vol. 1, 64-70 p.64-70 p.Conference paper (Other academic)
    Abstract [en]

    Muscle overuse is a frequent condition accompanying sports-related activities. There is a lack of knowledge concerning the importance of signal substances in situations when overuse leads to markedly affected muscle structure and muscle inflammation. Recent observations on signal substance systems for the muscle tissue in situations with muscle overuse, noted via the use of a rabbit model, are therefore here focused on. The signal substance systems are the tachykinin system, the TNF-alpha system and the glutamate system. The studies have shown that all three systems are involved in the myositis/muscle derangement processes that occur. A central finding is the notion that signal substances in all three systems become locally produced in the muscle tissue and that there is a marked presence of receptors for these in the inflammatory/affected muscle tissue. The relevance of the findings in relation to what is known for the systems and possibilities in treatment regimens are discussed. Th e findings suggest that signal substances, more than what has been previously considered, should be taken into consideration as factors of relevance in situations when overuse leads to structural derangement and muscle inflammation.

  • 39.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The Cholinergic System Can Be of Unexpected Importance in Osteoarthritis2012In: Priciples of Osteoarthritis, Its definition, character, derivation and modality-related recognition / [ed] Rotschild BM, InTech, 2012, 461-472 p.Chapter in book (Refereed)
    Abstract [en]

    The main belief is that joints such as the knee and ankle joints are not innervated by nerves with a cholinergic function. That includes  the assumption that these joints are not innervated by the vagus nerve (van Maanen et al., 2009a, see also Grimsholm et al., 2008). Accordingly, there is actually no morphologic proof of a cholinergic innervation of the knee joint, nor of the ankle joint. Despite this fact, it is shown that electrical and pharmacological stimulation of the vagus nerve has a diminishing effect on carragenan-induced paw inflammation in rats (Borovikova et al., 2000a) and that interference with the effects of the vagus nerve leads to effects on the knee joint arthritis as seen experimentally (van Maanen et al., 2009b). There are also other findings which  show the potential effects that interference with vagal effects has on joint inflammation. These will be discussed below. It is actually strange that interference with cholinergic effects, as via manpulations of the vagus nerve, has effects in knee joint inflamed synovium without presence of a vagal nerve innervation. One possibility is that the effects are indirect, via an occurrence of vagal effects on other sites such as the spleen (Huston et  al., 2006, see also van Maanen et al., 2009a). However, another possibility is that there is  a non-neuronal production of acetylcholine (ACh) within the synovial tissue itself. This has actually been shown to be the case (Grimsholm et al., 2008) (see  further in paragraph 3).

  • 40.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Further proof of the existence of a non-neuronal cholinergic system in the human Achilles tendon: Presence of the AChR alpha 7 receptor in tendon cells and cells in the peritendinous tissue2015In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 29, no 1, 195-200 p.Article in journal (Refereed)
    Abstract [en]

    Human tendon cells have the capacity for acetylcholine (ACh) production. It is not known if the tendon cells also have the potential for ACh breakdown, nor if they show expression of the nicotinic acetylcholine receptor AChR alpha 7 (alpha 7nAChR). Therefore, tendon tissue specimens from patients with midportion Achilles tendinopathy/tendinosis and from normal midportion Achilles tendons were examined. Reaction for the degradative enzyme acetylcholinesterase (AChE) was found in some tenocytes in only a few tendinopathy tendons, and was never found in those of control tendons. Tenocytes displayed more regularly alpha 7nAChR immunoreactivity. However, there was a marked heterogeneity in the degree of this reaction within and between the specimens. alpha 7nAChR immunoreactivity was especially pronounced for tenocytes showing an oval/widened appearance. There was a tendency that the magnitude of alpha 7nAChR immunoreactivity was higher in tendinopathy tendons as compared to control tendons. A stronger alpha 7nAChR immunoreactivity than seen for tenocytes was observed for the cells in the peritendinous tissue. It is likely that the alpha 7nAChR may be an important part of an auto-and paracrine loop of non-neuronal ACh that is released from the tendon cells. The effects may be related to proliferative and blood vessel regulatory functions as well as features related to collagen deposition. ACh can furthermore be of importance in leading to anti-inflammatory effects in the peritendinous tissue, a tissue nowadays considered to be of great relevance for the tendinopathy process. Overall, the findings show that tendon tissue, a tissue known to be devoid of cholinergic innervation, is a tissue in which there is a marked non-neuronal cholinergic system.

  • 41.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Norrgård, Örjan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novel information on the non-neuronal cholinergic system in orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases2009In: Orthopedic Reviews, ISSN 2035-8237, Vol. 1, no 1, 39-46 p.Article in journal (Refereed)
    Abstract [en]

    Anti-cholinergic agents are used in thetreatment of several pathological conditions.Therapy regimens aimed at up-regulatingcholinergic functions, such as treatment withacetylcholinesterase inhibitors, are also currentlyprescribed. It is now known that not onlyis there a neuronal cholinergic system but alsoa non-neuronal cholinergic system in variousparts of the body. Therefore, interference withthe effects of acetylcholine (ACh) broughtabout by the local production and release ofACh should also be considered. Locally producedACh may have proliferative, angiogenic,wound-healing, and immunomodulatory functions.Interestingly, cholinergic stimulationmay lead to anti-inflammatory effects. Withinthis review, new findings for the locomotorsystem of a more widespread non-neuronalcholinergic system than previously expectedwill be discussed in relation to possible newtreatment strategies. The conditions discussedare painful and degenerative tendon disease(tendinopathy/tendinosis), rheumatoid arthritis,and osteoarthritis.

  • 42.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Den kroniskt smärtande senan - histopatologi.2007In: Idrottsskador - frontlinjen inom behandling och rehablitering, 267-274 p.Article in journal (Refereed)
    Abstract [en]

    I denna artikel belyses de morfologiska förändringar man ser i Achilles- och patellarsena vid tendinos. Fokus riktas inte minst på nya fynd avseende utseenden för sencellerna (tenocyterna). Vidare ges en kortfattad beskrivning av vad man idag känner till avseende nervrelaterade aspekter för dessa senor hos människa. Det är sannolikt att kunskap om dessa är viktig för att man rätt ska förstå de smärtsymptom som föreligger vid tendinos och även de effekter som nyare tids behandlingar har vid dessa kroniska smärttillstånd.

  • 43.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bjur, Dennis
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Förändringar i kroniskt smärtande sena.2006In: Svensk Idrottsforskning: Organ för Centrum för Idrottsforskning, ISSN 1103-4629, Vol. 25, no 3, 8-10 p.Article in journal (Refereed)
    Abstract [en]

    Vad känner man till om de förändringar som sker i en kroniskt smärtande sena?

    Hur ser sencellerna ut och hur påverkas nerverna vid tendinos? I denna sammanställning kommer de förändringar man ser i Akilles- och patellarsena vid tendinos att belysas. Fokus riktas inte minst på nya fynd avseende utseenden för sencellerna (tenocyterna). Vidare ges en kortfattad beskrivning av vad man idag känner till avseende nervrelaterade aspekter för dessa senor hos människa. Det är sannolikt att kunskap om dessa är viktig för att man rätt ska förstå de smärtsymptom som föreligger vid tendinos och även de effekter som nyare tids behandlingar har vid dessa kroniska smärttillstånd.

  • 44.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons: studies on chemically unfixed as well as fixed specimens.2005In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 126, no 3, 173-181 p.Article in journal (Refereed)
    Abstract [en]

    It is not known as to whether the Achilles and patellar tendons contain neurokinin-1 (NK-1) receptors. This is a drawback when considering the fact that pain symptoms are frequent in these and as recent studies show that the pain symptoms might be cured via interference with blood vessel function. In the present study, the human Achilles and patellar tendons were examined concerning immunohistochemical expression of the NK-1 receptor. Chemically unfixed and fixed specimens, TRITC and PAP stainings and a battery of NK-1 receptor antibodies, including antibodies against the C-terminus and the N-terminal region, were utilized. NK-1 receptor immunoreaction could be detected in inner parts of the walls of large blood vessels and in the walls of small blood vessels. To some extent, NK-1 immunoreaction was also detectable in small nerve fascicles and in tenocytes. It was found to be of utmost importance to apply both chemically unfixed and fixed specimens. The use of chemically unfixed tissue was found advantageous in order to depict the immunoreactions in the blood vessel walls. The observations represent new findings and are of relevance as substance P (SP) is known to be of importance where neurogenic angiogenesis contributes to diseases and as SP on the whole has profound effects concerning blood vessel regulation.

  • 45.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Grimsholm, Ola
    University of Gothenburg.
    Dalén, Tore
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Measurements in the Blood of BDNF for RA Patients and in Response to Anti-TNF Treatment Help Us to Clarify the Magnitude of Centrally Related Pain and to Explain the Relief of This Pain upon Treatment2011In: International Journal of Inflammation, ISSN 2042-0099, E-ISSN 2042-0099, Vol. 2011, 650685- p.Article, review/survey (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin with functions related to neuronal survival/proliferation processes and inflammation. BDNF is also an important central pain mediator. The levels of BDNF have been found to be high for RA patients with severe disease and to become lowered in response to anti-TNF treatment. New information says that the levels of BDNF in the blood parallel the BDNF concentrations in the brain and that BDNF can pass the blood-brain barrier. Furthermore, most of the circulating BDNF is produced in the brain. Habitual and regular exercise, in contrast to temporary exercise, does also lead to a lowering of BDNF blood levels. Both anti-TNF treatment and habitual and regular exercise do have pain-relieving effects. It might be that the pain-relieving effect of anti-TNF treatment is related to an affection of central neuronal regions, hereby influencing BDNF production. Measurements of BDNF in the blood help us to clarify the magnitude of centrally related pain for RA patients and help us to explain the relief of this pain in response to anti-TNF treatment.

  • 46.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Renström, Lina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Purdam, Craig
    Gaida, James E.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. School of Primary Health Care, Monash University, Frankston, Australia.
    TNF-Alpha in the Locomotor System beyond Joints: High Degree of Involvement in Myositis in a Rabbit Model.2012In: International Journal of Rheumatology, ISSN 1687-9260, E-ISSN 1687-9279, Vol. 2012, 637452- p.Article in journal (Refereed)
    Abstract [en]

    The importance of TNF-alpha in arthritis is well documented. It may be that TNF-alpha is also markedly involved in muscle inflammation (myositis). An animal model where this can be investigated is needed. A newly developed rabbit myositis model involving pronounced muscle overuse and local injections of substances having proinflammatory effects was therefore used in the present study. The aim was to investigate the patterns of TNF-alpha expression in the developing myositis and to evaluate the usefulness of this myositis model for further TNF-alpha research. Human rheumatoid arthritis (RA) synovial tissue was examined as a reference. TNF-alpha immunoexpression and TNF-alpha mRNA, visualized via in situ hybridization, were detected in cells in the inflammatory infiltrates of the affected muscle (soleus muscle). Coexistence of TNF-alpha and CD68 immunoreactions was noted, suggesting that the TNF-alpha reactive cells are macrophages. Expression of TNF-alpha mRNA was also noted in muscle fibers and blood vessel walls in areas with inflammation. These findings demonstrate that TNF-alpha is highly involved in the myositis process. The model can be used in further studies evaluating the importance of TNF-alpha in developing myositis.

  • 47.
    Forsgren, Sture
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    In mid-portion Achilles tendinosis the plantaris tendon shows the same tendinosis-like morphological features and expression of the non-neuronal cholinergic system as the Achilles tendon itself2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, A3-A3 p.Article in journal (Other academic)
  • 48.
    Gaida, J
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. School of Primary Health Care, Monash University, Melbourne, Australia.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Cook, J
    School of Primary Health Care, Monash University, Melbourne, Australia.
    Decreased tumour necrosis factor alpha (tnf-a) in serum of patients with achilles tendinopathy: further evidence against the role of inflammation in the chronic stage2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 7, 597- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Altered expression of several cytokines and growth factors has been shown in biopsies of tendinopathy tissue. Biopsy studies are however challenged by capacity to obtain i) healthy tissue for comparison, ii) multiple samples to monitor cytokine dynamics, and iii) tissue from recent onset tendinopathy. An alternative is to study cytokines in blood samples. Whether cytokines in blood samples reflect tissue levels and the degree of tendinopathy is unknown.

    OBJECTIVE: To measure serum concentration of six cytokines and growth factors suggested to have a role in tendon response to load among individuals with chronic Achilles tendinopathy and controls.

    DESIGN: In this cross-sectional study, serum cytokine concentrations were measured from fasting blood samples on the BioPlex-200.

    SETTING: Sports Medicine Unit, Umeå University.

    PARTICIPANTS: Participants were recreationally active individuals. Achilles tendinopathy (n=22) was diagnosed on clinical criteria and confirmed with ultrasound examination. The control group (n=10) had no history of tendon pain and had normal ultrasound findings.

    INDEPENDENT VARIABLES: Serum concentration of tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), basic fibroblast growth factor (bFGF), platelet derived growth factor BB (PDGF-BB), interferon gamma (IFN-γ), and vascular-derived endothelial growth factor (VEGF) were the independent variables.

    MAIN OUTCOME MEASUREMENTS: A diagnosis of Achilles tendinopathy (yes/no) was defined as the key outcome variable prior to data collection.

    RESULTS: TNF-α concentration was lower in the tendinopathy group than the control group (P=.018); there were no other group differences.

    CONCLUSIONS: The observations indicate a lowering of the TNF-α concentration in the chronic phase of Achilles tendinopathy. As TNF-α levels are elevated in chronic inflammatory conditions, this reinforces that chronic Achilles tendinopathy is not an inflammatory disorder. Collecting a blood sample to study disease biomarkers leaves the tendon intact and therefore this design can be used to study cytokine dynamics with multiple sampling during disease progression and recovery.

  • 49.
    Gaida, James Edmund
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bagge, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Purdam, Craig
    Cook, Jill
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Evidence of the TNF-α system in the human Achilles tendon: expression of TNF-α and TNF receptor at both protein and mRNA levels in the tenocytes2012In: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 196, no 4, 339-352 p.Article in journal (Refereed)
    Abstract [en]

    Understanding adaption to load is essential for prevention and treatment of tendinopathy/tendinosis. Cytokine release in response to load is one mechanism involved in mechanotransduction. The cytokine tumor necrosis factor alpha (TNF-α) is implicated in tendinosis and can induce apoptotic effects via tumor necrosis factor receptor 1 (TNFR1). The complete absence of information concerning the TNF-α system in Achilles tendon is a limitation as mid-portion Achilles tendinosis is very frequent. Purpose: To examine expression patterns of TNF-α and its two receptors (TNFR1 and TNFR2) in human Achilles tendinosis and control tissue and to biochemically confirm the presence of TNF-α in tendinosis tissue. Methods: TNF-α and TNFR1 mRNA were detected via in situ hybridization. TNF-α, TNFR1, and TNFR2 were demonstrated immunohistochemically. Apoptosis markers were utilized. ELISA was used to detect TNF-α. Results: TNF-α and TNFR1 mRNA was detected in tenocytes of both tendinosis and control tendons. Tenocytes from both groups displayed specific immunoreactions for TNF-α, TNFR1, and TNFR2. The widened/rounded tenocytes of tendinosis samples exhibited the most intense immunoreactions. Apoptosis was detected in only a subpopulation of the tenocytes in tendinosis tissue. TNF-α was measurable in tendinosis tissue. Inflammatory cells were not seen. Conclusion: This is the first evidence of the existence of the TNF-α system in the human Achilles tendon. Findings are confirmed at mRNA and protein levels as well as biochemically. The TNF-α system was in principle confined to the tenocytes. The connection between tenocyte morphology and the expression pattern of TNF-α, TNFR1, and TNFR2 suggests that the TNF-α system may be involved in tenocyte activation in Achilles tendinosis.

  • 50.
    Gouveia-Figueira, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nording, Malin L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gaida, Jamie E.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Hakan
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Serum Levels of Oxylipins in Achilles Tendinopathy: An Exploratory Study2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, e0123114Article in journal (Refereed)
    Abstract [en]

    Background: Linoleic acid-derived oxidation products are found in experimental pain models. However, little is known about the levels of such oxylipins in human pain. In consequence, in the present study, we have undertaken a lipidomic profiling of oxylipins in blood serum from patients with Achilles tendinopathy and controls.

    Methodology/Principal findings: A total of 34 oxylipins were analysed in the serum samples. At a significance level of P<0.00147 (<0.05/34), two linoleic acid-derived oxylipins, 13-hydroxy-10E,12Z-octadecadienoic (13-HODE) and 12(13)-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME) were present at significantly higher levels in the Achilles tendinopathy samples. This difference remained significant when the dataset was controlled for age, gender and body-mass index. In contrast, 0/21 of the arachidonic acid- and 0/4 of the dihomo-γ-linolenic acid, eicosapentaenoic acid or docosahenaenoic acid-derived oxylipins were higher in the patient samples at this level of significance. The area under the Receiver-Operator Characteristic (ROC) curve for 12,13-DiHOME was 0.91 (P<0.0001). Levels of four N-acylethanolamines were also analysed and found not to be significantly different between the controls and the patients at the level of P<0.0125 (<0.05/4).

    Conclusions/Significance: It is concluded from this exploratory study that abnormal levels of linoleic acid-derived oxylipins are seen in blood serum from patients with Achilles tendinopathy. Given the ability of two of these, 9- and 13-HODE to activate transient receptor potential vanilloid 1, it is possible that these changes may contribute to the symptoms seen in Achilles tendinopathy.

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