Research ArticleBone

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.

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