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Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction

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Science Translational Medicine  16 Mar 2016:
Vol. 8, Issue 330, pp. 330ra35
DOI: 10.1126/scitranslmed.aac4351

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A surprising role for sclerostin in arthritis

Antibodies that block the activity of sclerostin, a bone destruction molecule, are in clinical trials for the treatment of osteoporosis. But these antibodies may not be safe for certain patients: those with inflammatory rheumatoid arthritis (RA). Wehmeyer et al. were surprised to find that sclerostin inhibition did not stop bone loss and actually aggravated disease in an animal model of RA that was dependent on tumor necrosis factor α (TNFα); two other rodent RA models with minimal or no dependence on this inflammatory cytokine were unaffected. The authors found that sclerostin blocks TNFα-induced p38 and NFκB activation—key steps in RA development. Thus, sclerostin appears to have a protective role in TNF-mediated chronic inflammation, and inhibiting it would be contraindicated in a subset of RA patients. This study therefore has immediate implications for current clinical trials involving patients with inflammatory bone loss.


Sclerostin, an inhibitor of the Wnt/β-catenin pathway, has anti-anabolic effects on bone formation by negatively regulating osteoblast differentiation. Mutations in the human sclerostin gene (SOST) lead to sclerosteosis with progressive skeletal overgrowth, whereas sclerostin-deficient (Sost−/−) mice exhibit increased bone mass and strength. Therefore, antibody-mediated inhibition of sclerostin is currently being clinically evaluated for the treatment of postmenopausal osteoporosis in humans. We report that in chronic TNFα (tumor necrosis factor α)–dependent arthritis, fibroblast-like synoviocytes constitute a major source of sclerostin and that either the lack of sclerostin or its antibody-mediated inhibition leads to an acceleration of rheumatoid arthritis (RA)–like disease in human TNFα transgenic (hTNFtg) mice with enhanced pannus formation and joint destruction. Inhibition of sclerostin also failed to improve clinical signs and joint destruction in the partially TNFα-dependent glucose-6-phosphate isomerase–induced arthritis mouse model, but ameliorated disease severity in K/BxN serum transfer–induced arthritis mouse model, which is independent of TNF receptor signaling, thus suggesting a specific role for sclerostin in TNFα signaling. Sclerostin effectively blocked TNFα- but not interleukin-1–induced activation of p38, a key step in arthritis development, pointing to a previously unrealized protective role of sclerostin in TNF-mediated chronic inflammation. The possibility of anti-sclerostin antibody treatment worsening clinical RA outcome under chronic TNFα-dependent inflammatory conditions in mice means that caution should be taken both when considering such treatment for inflammatory bone loss in RA and when using anti-sclerostin antibodies in patients with TNFα-dependent comorbidities.

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