Oncostatin M stimulates monocyte chemoattractant protein‐1‐ and interleukin‐1‐induced matrix metalloproteinase‐1 production by human synovial fibroblasts in vitro

Abstract

Objective. To measure levels of oncostatin M (OSM) in the synovial fluid of rheumatoid arthritis (FU) patients and to examine the activities of human OSM in the regulation of human synovial fibroblast (HSF) production of chemokines and matrix metalloproteinases (MMP-1 and MMP-3) in vitro.Methods. We examined the levels of OSM in the synovial fluids of patients with arthritis by an enzymelinked immunosorbent assay (ELISA). ELISA of cell culture supernatants and Northern blots were used to assess responses of HSF to interleukin-la (IL-la), OSM, and other members of the IL-6/leukemia inhibitory factor (IL-6/LIF) family of cytokines.Results. We detected variable levels of OSM antigen in 9 of 10 RA patient synovial fluids, but levelswere not detectable in 9 of 10 osteoarthritis (OA) patient fluids. Upon examining the responses of HSF in culture, OSM stimulated monocyte chemoattractant protein 1 (MCP-l), whereas RANTES secretion (regulated upon activation, normal T expressed and presumably secreted) was not altered by OSM alone. In IL-lainduced cells, OSM costimulation further enhanced MCP-1 release, but inhibited the release of RANTES and IL-8. Other members of the IL-6/LIF family of cytokines did not show these effects. OSM induced a small elevation of MMP-1 production over 2 and 3 days of stimulation (2-fold), and acted significantly to enhance IL-la-induced production of MMP-1 (to 8-fold Submitted for publication December 20, 1096; acccptcd in revised form July 15, 1097. and 9-fold at 48 and 72 hours, respectively). No effect of OSM was seen on MMP-3 secretion, either alone or in IL-la-costimulated cells.Conclusion. These results suggest that OSM has potentially important functions in the modulation of chemokine and metalloproteinase production by synovial cells of the joint.

Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis

“…So far, most studies corroborating the involvement of OSM in the development and progression of RA have highlighted its contribution to cartilage breakdown preferentially by up-regulation of MMPs and aggrecanases (18,20,22,26,46) as well as changes in the MMP:TIMP ratio in favor of MMPs (19,37). In this study, we identified OSM as the main regulator of CCL13 chemokine expression by SFs.…”

“…In vitro, OSM modulates matrix turnover in synoviocytes, chondrocytes, and cartilage explants, suggesting a pivotal role for OSM in the regulation of the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) at sites of destruction (20,(22)(23)(24). In addition, OSM has been demonstrated to act synergistically with proinflammatory cytokines such as IL-1␤, TNF␣, and IL-17 to induce extracellular matrix turnover (20,25,26).…”

“…Moreover, it has been shown that OSM has the capability to recruit immune cells to the site of inflammation. Neutrophils, for example, are recruited via the up-regulation of P-selectin (27), whereas OSM-induced expression of the chemokine CCL2 leads to the migration of monocytes (22).…”

Oncostatin M Receptor-β Signaling Limits Monocytic Cell Recruitment in Acute Inflammation

“…However in progressive chronic conditions OSM concentrations are more sustained and originate from activated macrophages and T lymphocytes (7,9). Such differences in OSM expression may have a considerable bearing on the inflammatory response since OSM synergizes with other inflammatory mediators including IL-1, TNF-␣, IL-6, IL-17, and IFN-␥ to affect degradation of extracellular matrix, leukocyte recruitment, and wound healing (16,20,21,32,33). However, based on OSM reconstitution studies in experimental models of disease, it is difficult to gauge whether OSM directs a protective or detrimental outcome in vivo (5,6,9,34,35).…”

Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

“…Besides tumor necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1)-family cytokines, there is increasing evidence that IL-6 family members and signaling pathways downstream of the common gp130 receptor subunit are important in the pathogenesis of both murine and human inflammatory arthritis (2). Oncostatin M (OSM) is a member of the IL-6 family, and many studies have demonstrated that it has a stimulatory role in the progression of RA (3,4). In a previous study, we demonstrated that OSM induced strong expression of CCL2, a potent chemoattractant for monocyte/macrophages, in human osteoblastic cells, at both the messenger RNA (mRNA) and protein levels (5), supporting the notion that OSM and osteoblasts have an important role in the mediation of inflammatory bone diseases.…”