Sclerostin Inhibition May Worsen Rheumatoid Arthritis Save

Sclerostin, an inhibitor of the Wnt/β-catenin pathway, negatively regulates osteoblast differentiation and has anti-anabolic effects on bone formation. Thus, inhibition of sclerostin is currently being studied as therapy for postmenopausal osteoporosis.

Wehmeyer et al. has found that inhibition of sclerostin may not be safe in som patients with inflammatory rheumatoid arthritis (RA), by finding that sclerostin inhibition did not stop bone loss and more importantly may aggravate disease. Using several animal models of RA they studied the effects of sclerostin inhibition.  

In one model of tumor necrosis factor α (TNFα) dependent arthritis, wherein fibroblast-like synoviocytes are a major source of sclerostin, antibody-mediated inhibition leads to enhanced pannus formation and joint destruction in these TNFα transgenic (hTNFtg) mice.

In other rodent models, sclerostin inhibition 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 TNF independent.

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. 

Thus, sclerostin appears to have a protective role in TNF-mediated chronic inflammation, and inhibiting it may be contraindicated in a subset of RA patients. This study therefore has immediate implications for current clinical trials involving patients with inflammatory bone loss.