umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. (Univ British Columbia, Dept Phys Therapy, Vancouver, BC, Canada and Vancouver Coastal Hlth & Res Inst, Ctr Hip Hlth & Mobil, Vancouver, BC, Canada and Sydney Med Sch, Sydney, NSW, Australia)
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
Vancouver Coastal Hlth & Res Inst, Ctr Hip Hlth & Mobil, Vancouver, BC, Canada. (Univ Calgary, McCaig Inst Bone & Joint Hlth, Calgary, AB, Canada)
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
Show others and affiliations
2013 (English)In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 31, no 1, 91-98 p.Article in journal (Refereed) Published
Abstract [en]

The loss of collagen organization is considered a hallmark histopathologic feature of tendinosis. At the cellular level, tenocytes have been shown to produce signal substances that were once thought to be restricted to neurons. One of the main neuropeptides implicated in tendinosis, substance P (SP), is known to influence collagen organization, particularly after injury. The aim of this study was to examine the influence of SP on collagen remodeling by primary human tendon cells cultured in vitro in three-dimensional collagen lattices. We found that SP stimulation led to an increased rate of collagen remodeling mediated via the neurokinin-1 receptor (NK-1 R), the preferred cell receptor for SP. Gene expression analysis showed that SP stimulation resulted in significant increases in MMP3, COL3A1 and ACTA2 mRNA levels in the collagen lattices. Furthermore, cyclic tensile loading of tendon cell cultures along with the administration of exogenous SP had an additive effect on MMP3 expression. Immunoblotting confirmed that SP increased MMP3 protein levels via the NK-1 R. This study indicates that SP, mediated via NK-1 R, increases collagen remodeling and leads to increased MMP3 mRNA and protein expression that is further enhanced by cyclic mechanical loading.

Place, publisher, year, edition, pages
HOBOKEN, NJ, USA: Wiley-Blackwell, 2013. Vol. 31, no 1, 91-98 p.
Keyword [en]
tendinopathy, tendinosis, collagen, myofibroblasts, neurokinin-1 receptor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-63758DOI: 10.1002/jor.22191ISI: 000311568700013OAI: oai:DiVA.org:umu-63758DiVA: diva2:585623
Available from: 2013-01-10 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Influence of neuromodulators and mechanical loading on pathological cell and tissue characteristics in tendinosis
Open this publication in new window or tab >>Influence of neuromodulators and mechanical loading on pathological cell and tissue characteristics in tendinosis
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Betydelsen av neuromodulatorer och mekanisk belastning för cell- och vävnadsförändringar vid tendinos
Abstract [en]

Background: Tendinosis is a painful chronic, degenerative condition characterized by objective changes in the tissue structure of a tendon. Hallmark features in tendinosis tendons include increased number of cells (hypercellularity), extracellular matrix (ECM) degradation and disorganized collagen. The progression of these pathological changes seen in tendinosis is neither well characterized nor fully understood.

Studies have suggested that there are biochemical and mechanical elements involved in tendinosis. From a biochemical perspective, studies have shown that the tendon cells, tenocytes, produce a number of neuronal signal substances/neuromodulators, such as substance P (SP) and acetylcholine (ACh), traditionally thought to be confined to the nervous system. Furthermore, it has been shown that the expression of these neuromodulators is elevated in tendinosis tendons as compared to normal healthy tendons. Interestingly, studies on other tissue types have revealed that both SP and ACh can induce tissue changes seen in tendinosis, such as hypercellularity and collagen disorganization. From a mechanical angle, it has been suggested that overload of tendons, including extensive strain on the primary tendon cells (tenocytes), causes the degenerative processes associated with tendinosis. In vivo studies have shown that in overloaded tendons, the presence of neuromodulators is elevated, not least SP, which also precedes the development of the tissue changes seen in tendinosis. This further supports the importance of combining biochemical factors and mechanical factors in the pathogenesis of tendinosis.

Hypotheses: In this thesis project, we hypothesize: 1) that neuromodulators, such as SP and ACh when stimulating their preferred receptors, the neurokinin 1 (NK-1 R) and muscarinic receptors (mAChRs), respectively, can cause increased tenocyte proliferation; 2) that the effects of SP and ACh on tenocyte proliferation converge mechanistically via a shared signalling pathway; 3) that mechanical loading of tenocytes results in increased production of SP by the tenocytes; and 4) that SP enhances collagen remodelling by tenocytes via NK-1 R.

Model system: In vitro studies offer insight into the function of healthy tendon matrix and the etiology of tendinopathy. Using a cell culture model of human primary tendon cells, highly controlled experiments were performed in this thesis project to study a subset of biological and mechanical parameters that are implicated in tendinosis. The FlexCell® Tension System was used to study the influence of mechanical loading on tenocytes. As well, a collagen gel contraction assay was used to examine the intrinsic ability of tenocytes to reorganise type I collagen matrices under the influence of the neuromodulator SP.

Results: The studies showed that exogenous administration of SP and ACh results in increased tenocyte proliferation that is mediated via activation of the ERK1/2 mitogenic pathway when the preferred receptors of SP and ACh, the NK-1 R and mAChRs, respectively, are stimulated. Furthermore, the studies resulted in the novel finding that SP and ACh both converge mechanistically via transforming growth factor (TGF)-β1 and that a negative feedback mechanism is present in which TGF-β1 downregulates the expression of mAChRs and NK-1 R. The studies also showed that SP can increase collagen remodelling and upregulate expression of genes related to tendinosis. Finally, it was established that tenocytes are mechanoresponsive by showing that cyclic mechanical loading increases the expression of SP by human tenocytes.

Conclusions: This thesis work concludes that stimulation of NK-1 R and mAChRs results in proliferation of human tenocytes, which both involve the ERK1/2 signalling pathway. It also shows that SP and ACh converge mechanistically via TGF-β1 in their contribution to tenocyte proliferation. The role of hypercellularity in tendinosis tissue is unknown. Possibly, it has different roles at different stages of the disease. The findings also show that SP increases collagen remodelling, suggesting that increased SP not only results in hypercellularity but also contributes to the collagen morphology in tendinosis.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1882
Keyword
substance P, acetylcholine, transforming growth factor, neuromodulators, mechanical loading, tendinosis
National Category
Cell and Molecular Biology
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-131390 (URN)978-91-7601-666-4 (ISBN)
Public defence
2017-03-10, KBC-huset, sal KB.E3.01, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 521-2013-2612Swedish Society of Medicine, SLS-504541Swedish National Centre for Research in Sports, P2013-0055
Available from: 2017-02-17 Created: 2017-02-13 Last updated: 2017-03-16Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Fong, GloriaBackman, Ludvig J.Danielson, Patrik
By organisation
Anatomy
In the same journal
Journal of Orthopaedic Research
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 86 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf