TSG‐6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergistic with osteoprotegerin

Abstract

Objective. TSG-6 (the product of tumor necrosis factor [TNF]-stimulated gene 6) has a potent inhibitory effect on RANKL-mediated bone erosion. The aim of this study was to compare the activity of TSG-6 with that of osteoprotegerin (OPG) and to investigate its role as an autocrine modulator of cytokine-mediated osteoclast formation/activation. We also determined TSG-6 expression in inflammatory joint disease.Methods. The effects of TSG-6, OPG, and the inflammation mediators TNF␣, interleukin-1 (IL-1), and IL-6 on the formation of osteoclasts from peripheral blood mononuclear cells and synovial fluid (SF) macrophages were determined by tartrateresistant acid phosphatase staining. Lacunar resorption and filamentous actin ring formation were measured as indicators of osteoclast activity. The amount of TSG-6 in culture media or SF was quantified by enzyme-linked immunosorbent assay, and expression of TSG-6 in synovial tissue was assessed by immunohistochemistry.Results. TSG-6 acted in synergy with OPG to inhibit RANKL-mediated bone resorption and was produced by osteoclast precursors and mature osteoclasts in response to TNF␣, IL-1, and IL-6. Expression of TSG-6 correlated with inhibition of lacunar resorption; this effect was ameliorated by an anti-TSG-6 antibody. The level of TSG-6 protein was determined in SF from patients with various arthritides; it was highest in patients with inflammatory conditions such as rheumatoid arthritis, in which it correlated with the amount of TSG-6 immunostaining in the synovium. TSG-6 inhibited the activation but not the formation of osteoclasts from SF macrophages.Conclusion. In the presence of inflammatory cytokines, osteoclasts produced TSG-6 at concentrations that are sufficient to inhibit lacunar resorption. This may represent an autocrine mechanism to limit the degree of bone erosion during joint inflammation.

Gene Expression Profiling in Peripheral Blood Cells and Synovial Membranes of Patients with Psoriatic Arthritis

“…In addition the following upregulated genes may support bone growth by interfering with osteoclast activity: tumor necrosis factor, alpha-induced protein 6, TNFAIP6/TSG6 (FC 4.84) [89], and serpin peptidase inhibitor, clade F member 1, SERPINF1/PEDF (FC 4.77).…”

Therapeutic Effect of TSG-6 Engineered iPSC-Derived MSCs on Experimental Periodontitis in Rats: A Pilot Study

“…7) also showed anti-bone resorption of TSG-6-modified iPS-MSCs by suppressing osteoclast formation and inhibiting alveolar bone resorption in this investigation. Previous study has shown that TSG-6 could regulate bone remodeling though the inhibition of osteoclast activity and the synergistic formation with osteoprotegerin [18], [19]. They indicated an autocrine mechanism of TSG-6 inhibiting osteoclasts activation; that is, osteoclast precursors and mature osteoclasts produced TSG-6 in response to pro-inflammatory cytokines (i.e.…”

“…Among these factors, the most interesting was tumor necrosis factor alpha-stimulated gene-6 (TSG-6) [12], which has been extensively studied in articular joint diseases [13]–[15]. The anti-inflammatory and chondroprotective effects of TSG-6 have been reported in numerous animal models [16]–[19]. However, the combined effect of MSCs and TSG-6 has not been investigated.…”

Incorporation of Pentraxin 3 into Hyaluronan Matrices Is Tightly Regulated and Promotes Matrix Cross-linking

“…TSG-6 is composed of two domains: the Link module with its HA-binding domain (31–34) and the CUB module (Protein Data Bank entry 2WNO) (35). In some cases, the Link module has been found to elicit biological responses similar to full-length TSG-6 (36–39). However, this is not the case for the interaction with HA; the Link module alone binds to HA in a simple manner, whereas the full-length protein binds to HA cooperatively, due to HA-induced TSG-6 oligomerization, a process that leads to cross-linking of HA (40).…”