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Neuropeptides and neurotrophins in arthritis: studies on the human and mouse knee joint
Umeå University, Faculty of Medicine, Integrative Medical Biology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuropeptides, such as substance P (SP) and bombesin/gastrin-releasing peptide (BN/GRP), and neurotrophins are involved in neuro-immunomodulatory processes and have marked trophic, growth-promoting and inflammation-modulating properties. The impact of these modulators in rheumatoid arthritis (RA) is, however, unclear. An involvement of the innervation, including the peptidergic innervation, is frequently proposed as an important factor for arthritic disease. Many patients with RA, but not all, benefit from treatment with anti-TNF medications.

The studies presented here aimed to investigate the roles of neuropeptides, with an emphasis on BN/GRP and SP, and neurotrophins, especially with attention to brain-derived neurotrophic factor (BDNF), in human and murine knee joint tissue. The expression patterns of these substances and their receptors in synovial tissue from patients with either RA or osteoarthritis (OA) were studied in parallel with the levels of these factors in blood and synovial fluid from patients with RA and from healthy controls. Correlation studies were also performed comparing the levels of neuropeptides with those of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)]. Furthermore, the impact of anti-TNF treatment on the levels of BDNF in blood was investigated. In a murine model of RA, the expression of these substances on articular chondrocytes along with their expression in synovial tissue was investigated.

The expression of BN/GRP in human synovial tissue was confined to fibroblast-like and mononuclear-like cells whereas SP was detected in nerve-related structures. Receptors for these neuropeptides (GRP-R and NK-1R) were frequently present in blood vessel walls, and on fibroblast-like and mononuclear-like cells. The expression of BDNF and its receptors, p75 neurotrophin receptor and TrkB, was mainly confined to nerve structures. The levels of SP, and particularly those of BN/GRP, in synovial fluid and peripheral blood correlated with the levels of pro-inflammatory cytokines. There were clearly more correlations between SP-BN/GRP and inflammatory parameters than between BDNF and these factors. Plasma levels of BDNF were decreased following anti-TNF-treatment. In the joints of the murine model, there was a marked expression of neurotrophins, neurotrophin receptors and NK-1R/GRP-R in the articular chondrocytes. The expression was down-regulated in the arthritic animals. A neurotrophin system was found to develop in the inflammatory infiltrates of the synovium in the arthritic mice.

The results presented suggest that there is a local, and not nerve-related, supply of BN/GRP in the human synovial tissue. Furthermore, BN/GRP and SP have marked effects in the synovial tissue of patients with RA, i.e., there were abundant receptor expressions, and these neuropeptides are, together with cytokines, likely to be involved in the neuro-immunomodulation that occurs in arthritis. The observations do on the whole suggest that the neuropeptides, rather than BDNF, are related to inflammatory processes in the human knee joint. A new effect of anti-TNF treatment; i.e., lowering plasma levels of BDNF, was observed. Severe arthritis, as in the murine model, lead to a decrease in the levels of neurotrophin, and neurotrophin and neuropeptide receptor expressions in the articular cartilage. This fact might be a drawback for the function of the chondrocytes. Certain differences between the expression patterns in the synovial tissue of the murine model and those of human arthritic synovial tissue were noted. It is obvious that local productions in the synovial tissue, nerve-related supply in this tissue and productions in chondrocytes to different extents occur for the investigated substances.

Place, publisher, year, edition, pages
Umeå Universitet/Integrativ medicinsk biologi , 2008. , 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1212
Keyword [en]
neuropeptides, neurotrophins, bombesin/gastrin-releasing peptide, substance P, brain-derived neurotrophic factor, synovial tissue, knee joint, rheumatoid arthritis
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1863ISBN: 978-91-7264-647-6 (print)OAI: oai:DiVA.org:umu-1863DiVA: diva2:142233
Public defence
2008-10-17, Biologihusets stora föreläsningssal, BiA 201, Biologihuset, IMB avd Anatomi, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2008-09-29 Created: 2008-09-29 Last updated: 2009-04-22Bibliographically approved
List of papers
1. Observations favouring the occurrence of local production and marked effects of bombesin/gastrin-releasing peptide in the synovial tissue of the human knee joint: comparisons with substance P and the NK-1 receptor.
Open this publication in new window or tab >>Observations favouring the occurrence of local production and marked effects of bombesin/gastrin-releasing peptide in the synovial tissue of the human knee joint: comparisons with substance P and the NK-1 receptor.
2008 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 42, no 2, 133-145 p.Article in journal (Refereed) Published
Abstract [en]

We have previously shown that levels of the neuropeptides substance P (SP) and bombesin/gastrin-releasing peptide (BN/GRP) in blood and synovial fluid correlate with levels of pro-inflammatory cytokines in patients with rheumatoid arthritis (RA). It is well-established that SP is present in nerve endings in the synovium whilst the source of BN/GRP in human joints is completely unknown. Nor is it known whether GRP-receptors (GRP-R) are present in human synovial tissue. This study aimed to investigate the expression pattern of SP, BN/GRP and their receptors (NK-1R and GRP-R) in synovial tissue. Synovial tissue specimens from patients with RA or osteoarthritis (OA) were processed for immunohistochemistry, in situ hybridisation and ELISA. The results show the presence of BN/GRP, but not SP, in cells in the synovial tissue at both the protein and mRNA level. We did not find immunoreactive BN/GRP in nerve structures. NK-1R and GRP-R were also expressed at both protein and mRNA levels in cells associated with blood vessels and cells in the interstitial tissue. ELISA analyses revealed both SP and BN/GRP to be present in synovial tissue extracts and that synovial levels of SP were higher in RA patients than those with OA. Our results indicate that BN/GRP is produced by non-neuronal cells in the synovial tissue. Furthermore, both BN/GRP and SP may exert their effects on the synovial tissue through the respective receptors. These results suggest that BN/GRP and SP may modulate inflammation and vascular events, and possibly healing processes in the synovium. Finally, nerves should not be considered as the source of BN/GRP in synovial tissue although this peptide is presumably intimately involved functionally in synovial tissue, a previously unrecognised fact.

Identifiers
urn:nbn:se:umu:diva-20593 (URN)10.1016/j.npep.2007.12.008 (DOI)18289674 (PubMedID)
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2017-12-13
2. BDNF in RA: Downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters.
Open this publication in new window or tab >>BDNF in RA: Downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters.
2008 (English)In: Clinical Rheumatology, ISSN 0770-3198, Vol. 27, no 10, 1289-1297 p.Article in journal (Refereed) Published
Abstract [en]

The involvement of brain-derived neurotrophic factor (BDNF) in rheumatoid arthritis (RA) is largely unknown. The distribution of BDNF and its associated receptors, TrkB and p75, in the synovial tissue of patients with RA was examined and contrasted with that in patients with osteoarthritis (OA). Additionally, levels of BDNF in both synovial tissue and synovial fluid were measured. Furthermore, the effects of anti-tumour necrosis factor (anti-TNF; infliximab) treatment on BDNF levels in the plasma of RA patients were analysed. Cells in the synovium showed immunoreactivity for BDNF and BDNF-, p75- and TrkB-receptor immunoreactions were seen in nerve fibres of nerve fascicles and in association with sensory corpuscles. The levels of BDNF in synovial tissue were not correlated with the number of inflammatory cells observed microscopically or with levels of TNFα. Nor did the BDNF levels in synovial fluid correlate with erythrocyte sedimentation rate (ESR) or white blood cell counts. Anti-TNF treatment lead to a decrease in plasma levels of BDNF 14 weeks after the initiation of anti-TNF therapy, i.e., 8 weeks after the last infusion. Higher levels of BDNF were observed in RA patients at baseline compared with those for healthy individuals. However, the levels of BDNF in plasma of patients treated with anti-TNF did not correlate with the changes in ESR or a disease activity score. The clinical significance of this study is that anti-TNF treatment influences plasma levels of BDNF although there was no evidence that BDNF levels correlate with inflammatory parameters in either infliximab-treated or non-infliximab-treated patients with RA. Instead it is likely that sources other than inflammatory cells, including nerve structures, are important sources of BDNF and that the effects of anti-TNF treatment on BDNF levels may be related to effects on circulating and various local cells and/or BDNF-containing neurons.

Identifiers
urn:nbn:se:umu:diva-11150 (URN)10.1007/s10067-008-0910-4 (DOI)18484150 (PubMedID)
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2011-04-07Bibliographically approved
3. Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis.
Open this publication in new window or tab >>Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis.
2005 (English)In: Arthritis research & therapy, ISSN 1478-6362, Vol. 7, no 3, R416-426 p.Article in journal (Refereed) Published
Abstract [en]

It is well known that cytokines are highly involved in the disease process of rheumatoid arthritis (RA). Recently, targeting of neuropeptides has been suggested to have potential therapeutic effects in RA. The aim of this study was to investigate possible interrelations between five neuropeptides (bombesin/gastrin-releasing peptide (BN/GRP), substance P (SP), vasoactive intestinal peptide, calcitonin-gene-related peptide, and neuropeptide Y) and the three cytokines tumour necrosis factor (TNF)-alpha, IL-6, and monocyte chemoattractant protein-1 in synovial fluid of patients with RA. We also investigated possible interrelations between these neuropeptides and soluble TNF receptor 1 in serum from RA patients. Synovial fluid and sera were collected and assayed with ELISA or RIA. The most interesting findings were correlations between BN/GRP and SP and the cytokines. Thus, in synovial fluid, the concentrations of BN/GRP and SP grouped together with IL-6, and SP also grouped together with TNF-alpha and monocyte chemoattractant protein-1. BN/GRP and SP concentrations in synovial fluid also grouped together with the erythrocyte sedimentation rate. In the sera, BN/GRP concentrations and soluble TNF receptor 1 concentrations were correlated. These results are of interest because blocking of SP effects has long been discussed in relation to RA treatment and because BN/GRP is known to have trophic and growth-promoting effects and to play a role in inflammation and wound healing. Furthermore, the observations strengthen a suggestion that combination treatment with agents interfering with neuropeptides and cytokines would be efficacious in the treatment of RA. In conclusion, BN/GRP and SP are involved together with cytokines in the neuroimmunomodulation that occurs in the arthritic joint.

Identifiers
urn:nbn:se:umu:diva-22034 (URN)10.1186/ar1503 (DOI)15899028 (PubMedID)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2011-01-18
4. Are neuropeptides important in arthritis? Studies on the importance of bombesin/GRP and substance P in a murine arthritis model.
Open this publication in new window or tab >>Are neuropeptides important in arthritis? Studies on the importance of bombesin/GRP and substance P in a murine arthritis model.
Show others...
2007 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1110, 525-538 p.Article in journal (Refereed) Published
Abstract [en]

Interference with the effects of neuropeptides may be of potential therapeutic value for the treatment of rheumatoid arthritis (RA). Two neuropeptides that can be discussed in this context are bombesin/gastrin-releasing peptide (BN/GRP) and substance P (SP). In order to obtain new information on the possible importance of these two peptides, the patterns of immunohistochemical expression of BN/GRP and SP and their related receptors in the mouse knee joint from healthy and arthritic mice were examined. Positive staining for GRP receptor and the SP preferred receptor (the neurokinin-1 receptor [NK-1 R]) was observed in articular chondrocytes. On the whole, there was a decrease in immunoreactions for both the GRP- and the NK-1 receptors in the articular chondrocytes in joints exhibiting severe arthritis. Staining for BN/GRP and GRP receptor was seen in the inflammatory infiltrates of the arthritic joints. New evidence for the occurrence of marked effects of BN/GRP concerning both the articular chondrocytes and the inflammatory process is obtained in this study. With these findings and previous observations of neuropeptide expression patterns and functions we discuss the possibility that interventions with the effects of BN/GRP, SP, and other neuropeptides might be worthwhile in RA.

Identifiers
urn:nbn:se:umu:diva-22038 (URN)10.1196/annals.1423.056 (DOI)17911468 (PubMedID)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2017-12-13
5. Expression patterns of neurotrophins and neurotrophin receptors in articular chondrocytes and inflammatory infiltrates in knee joint arthritis.
Open this publication in new window or tab >>Expression patterns of neurotrophins and neurotrophin receptors in articular chondrocytes and inflammatory infiltrates in knee joint arthritis.
2008 (English)In: Cells, tissues, organs, ISSN 1422-6421, Vol. 188, no 3, 299-309 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: It is likely that neurotrophins (NTs) are of great importance for the articular cartilage and the inflammation process in arthritis. METHODS: The immunohistochemical expression of the NTs nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and the associated receptors p75, TrkA and TrkB was examined in the knee joint of arthritic and healthy mice. RESULTS: Immunoreactions for NGF and BDNF were detected in cells and nerve fiber varicosities in the inflammatory infiltrates of the synovial tissue of arthritic joints but not in synovial tissue of controls. p75-immunoreactive nerve fiber-like strands were detected in inflammatory infiltrates. Immunostaining for NGF, BDNF, p75, TrkA and TrkB was noted in articular chondrocytes. There was a statistically significant decrease in reactions for NGF (p < 0.001), TrkA (p = 0.001) and p75 (p < 0.001) in articular chondrocytes in joints exhibiting severe arthritis. CONCLUSION: The findings show that an NT system develops in inflammatory infiltrates of the synovial tissue. Furthermore, most interestingly, autocrine/paracrine effects appear to exist concerning NTs for the articular chondrocytes. The downregulated expression of NGF and NT receptors in articular chondrocytes in arthritis is a new aspect concerning the involvement of NTs in cartilage.

Identifiers
urn:nbn:se:umu:diva-22040 (URN)10.1159/000121432 (DOI)18349525 (PubMedID)
Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2011-03-30

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