Rheumatoid Arthritis: Grimsholm O

Forsgren S, Grimsholm O, Jönsson M, Alfredson H, Danielson P. · Department of Integrative Medical Biology, Section for Anatomy, Umeå University, SE-901 87 Umeå, Sweden. · Life Sci. · Pubmed #19409915 No free full text.

Abstract: For certain parts of the body, it is nowadays accepted that there is a cholinergic system that is not related to cholinergic innervation, i.e. a non-neuronal cholinergic system. It might be argued that this system is of minor importance. New information obtained shows, however, that the non-neuronal cholinergic system is more widely distributed in the body than what is previously recognised. In recent studies, the existence of such a system has thus been shown for human tendons, especially in chronically painful situations (tendinopathy/tendinosis), in the synovial tissue of patients with rheumatoid arthritis and osteoarthritis, and in the mucosa of ulcerative colitis patients. There is evidence of both acetylcholine (ACh) production and a marked existence of muscarinic (M2) ACh receptors in these situations. The non-neuronal cholinergic system may be involved in the establishment of a 'cholinergic anti-inflammatory pathway' and in proliferative and tissue reorganisation processes via autocrine/paracrine effects. The new information obtained suggests that this system plays an important functional role in chronically painful tendons and in inflammatory conditions. The findings of such a system in various parts of the body, when taken together, show that not only should the classical neuronal cholinergic system be considered in discussion of the cholinergic influences in the body. Additionally, the production of ACh in local cells in the tissues represents an important extra supply of the transmitter. ACh effects can be obtained whether or not there is a cholinergic innervation in the tissue.

Grimsholm O, Rantapää-Dahlqvist S, Dalén T, Forsgren S. · Section for Anatomy, Department of Integrative Medical Biology, Umeå University, SE-901 87 Umeå, Sweden. · Neurosci Lett. · Pubmed #18621096 No free full text.

Abstract: The cholinergic anti-inflammatory pathway is a newly discovered pathway. Another recent concept is the existence of a non-neuronal cholinergic system that has, so far, been defined for human tendons, intestine, airways and urinary bladder. The existence of such a system in joint synovial tissue is yet to be described. We therefore aimed to investigate the expression of choline acetyltransferase (ChAT) at both the protein and mRNA level using immunohistochemistry and in situ hybridisation, in human knee synovial tissue from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. The biopsy samples were collected from patients undergoing knee prosthetic surgery. Our results show that both ChAT protein and mRNA is expressed in fibroblast-like and mononuclear-like cells, and to some extent in blood vessel walls in the synovial tissue. The mononuclear-like cells showing ChAT expression were scattered throughout the synovial tissue or located in association with lymphoid aggregates. Thus, we present the first evidence of the existence of a marked non-neuronal cholinergic system in human synovial tissue. The existence of this system could lead to the development of alternative medications to those currently in use. The system might function as a cholinergic anti-inflammatory pathway in synovial tissue. Our observations show that synovial tissue of patients with marked RA or OA, a tissue in which cholinergic innervation is not proven to exist, is supplied with acetylcholine via production in non-neuronal cells within the tissue.

Grimsholm O, Rantapää-Dahlqvist S, Dalén T, Forsgren S. · Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden. · Clin Rheumatol. · Pubmed #18484150 No free full text.

Abstract: 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 TNFalpha. 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.

Grimsholm O, Rantapää-Dahlqvist S, Dalén T, Forsgren S. · Section for Anatomy, Department of Integrative Medical Biology, Umeå University, and Department of Rheumatology, Umeå University Hospital, SE-901 87 Umeå, Sweden. · Neuropeptides. · Pubmed #18289674 No free full text.

Abstract: 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.

Grimsholm O, Guo Y, Ny T, Rantapää-Dahlqvist S, Forsgren S. · Department of Integrative Medical Biology, Section for Anatomy, Umeå University, SE-901 87 Umeå, Sweden. · Ann N Y Acad Sci. · Pubmed #17911468 No free full text.

Abstract: 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.

Grimsholm O, Rantapää-Dahlqvist S, Forsgren S. · Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden. · Arthritis Res Ther. · Pubmed #15899028 links to  free full text

Abstract: 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.