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.

中文翻译：

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抑制JAK可以增加稳态条件下的骨量，并通过刺激成骨细胞功能改善病理性骨质流失。

Janus激酶（JAK）介导的细胞因子信号传导已成为治疗诸如类风湿关节炎（RA）等炎症疾病的重要治疗靶标。因此，JAK抑制剂构成了新的一类药物，其中托法替尼和baricitinib已被批准用于RA的治疗。关节周围骨侵蚀在RA发病机理中起重要作用。但是，尽管对JAK抑制（JAKi）的免疫调节方面有很好的定义，但目前对JAKi如何影响骨稳态的认识有限。这里，我们评估了JAK抑制剂tofacitinib和baricitinib对（i）稳态条件下的小鼠或因（ii）雌激素缺乏症（卵巢切除术）或（iii）炎症（关节炎）引起的骨丢失小鼠的骨表型的影响（i）评估JAKi对骨骼代谢的影响是否需要非炎性/炎性挑战。在这三个模型中，JAKi均增加了骨量，这与降低血清中NF-κB配体/骨保护素受体活化剂的比例一致。在体外，分析了tofacitinib和baricitinib对破骨细胞和成骨细胞分化的影响。JAKi显着增加了成骨细胞功能（P <0.05），但对破骨细胞没有直接作用。另外，在暴露于JAKi的成骨细胞中进行了mRNA测序和独创性途径分析，结果揭示了成骨细胞功能标记（如骨钙蛋白和Wnt信号传导）的上调作用。JAKi的合成代谢作用通过β-catenin的稳定来说明。在关节炎患者中，JAKi可以诱导骨合成代谢作用，这可以通过关节炎骨侵蚀的修复得到证明。结果支持JAKi是增强成骨细胞功能和骨骼形成的有效治疗工具。