Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction

Abstract

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.

Role and mechanism of action of sclerostin in bone

“…Sclerostin has also been detected in calcifying vascular tissues (26–28). Moreover, fibroblast-like synoviocytes have been also proposed to be a major source of sclerostin in rheumatoid arthritis (29), and multiple myeloma cells appear to also express the protein (30;31), as it will be discussed below. All this evidence notwithstanding, the contribution of non-osteocytic sclerostin to the skeletal effects attributed to this protein remains to be determined.…”

Sclerostin expression and functions beyond the osteocyte

“…Sclerostin expression has also been reported to be altered in rheumatic joint diseases (14, 23, 24);…”

TRAF6 regulates the effects of polarized maturation of tolerability: Marrow-derived dendritic cells on collagen-induced arthritis in mice

“…The latter are regarded as effector cells responsible for cartilage and bone destruction in RA. Then, RA leads to deformity and evenutally to significant functional decline (11,12). Following in-depth study of the pathogenesis of RA, most scholars agree that the abnormalities of autoreactive T cells induced by antigen-presenting cells (APCs) are the central link in the pathogenesis of RA (13)(14)(15).…”