Research ArticleBone

JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function

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Science Translational Medicine  12 Feb 2020:
Vol. 12, Issue 530, eaay4447
DOI: 10.1126/scitranslmed.aay4447

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Boosting osteoblasts to battle bone erosion

Inhibitors of Janus kinase (JAK) reduce inflammation and are approved to treat rheumatoid arthritis; however, the direct effects of inhibitors on bone remain unclear. Adam et al. found that JAK inhibitors increased bone mass in mice under homeostatic conditions and mitigated bone loss in a mouse model of osteoporosis. Mice with inflammatory bone loss mimicking rheumatoid arthritis had reduced bone erosions after treatment with JAK inhibitors, and two patients with rheumatoid arthritis treated with tofacitinib showed similar results. The authors determined that JAK inhibitors induced bone repair by altering gene expression and increasing activity of osteoblasts, supporting use of inhibitors as potential osteoanabolics.

Abstract

Janus kinase (JAK)–mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.

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