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Updated: Jun 6, 2026
Osteoclast Derivation from Mouse Bone Marrow
Published on: November 6, 2014
TSG-6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergistic with osteoprotegerin
David J Mahoney1, Catherine Swales, Nicholas A Athanasou
1University of Oxford, Oxford, UK.
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 TNFα, 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 tartrate-resistant 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 TNFα, 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.
Insights
Tumor necrosis factor-stimulated gene 6 (TSG-6) inhibits bone erosion by osteoclasts, acting in synergy with osteoprotegerin (OPG). This protein is produced by osteoclasts during inflammation, potentially limiting joint damage.
Area of Science:
- Immunology
- Rheumatology
- Bone Biology
Background:
- Tumor necrosis factor-stimulated gene 6 (TSG-6) is known to inhibit RANKL-mediated bone erosion.
- Osteoclast formation and activation are critical processes in bone remodeling and are implicated in inflammatory joint diseases.
Purpose of the Study:
- To compare the bone erosion inhibitory activity of TSG-6 with osteoprotegerin (OPG).
- To investigate the role of TSG-6 as an autocrine modulator of cytokine-induced osteoclast formation and activation.
- To assess TSG-6 expression in the context of inflammatory joint disease.
Main Methods:
- Osteoclastogenesis assays using peripheral blood mononuclear cells and synovial fluid macrophages.
- Measurement of osteoclast activity through tartrate-resistant acid phosphatase staining, lacunar resorption, and actin ring formation.
- Quantification of TSG-6 protein levels via ELISA and assessment of synovial tissue expression using immunohistochemistry.
Main Results:
- TSG-6 synergized with OPG to inhibit RANKL-mediated bone resorption.
- Osteoclasts produced TSG-6 in response to inflammatory cytokines (TNFα, IL-1, IL-6).
- TSG-6 expression correlated with reduced lacunar resorption, and this effect was blocked by an anti-TSG-6 antibody. Higher TSG-6 levels were observed in synovial fluid and tissue of patients with inflammatory arthritis, particularly rheumatoid arthritis.
- TSG-6 inhibited osteoclast activation but not their formation from synovial fluid macrophages.
Conclusions:
- Osteoclasts generate TSG-6 in inflammatory conditions at levels sufficient to inhibit bone resorption.
- This suggests an autocrine mechanism where TSG-6 limits osteoclast-mediated bone erosion during joint inflammation.
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