JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function
JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function
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DOI：
10.1126/scitranslmed.aay4447
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发表时间：
2020-02-12
影响因子：
17.1
通讯作者：
Hueber, Axel J.
中科院分区：
文献类型：
--
作者：
Adam, Susanne;Simon, Nils;Hueber, Axel J.
Janus激酶(JAK)介导的细胞因子信号转导已成为治疗类风湿性关节炎(RA)等炎症性疾病的重要靶点。相应地，JAK抑制剂组成了一类新的药物，其中托法替尼和巴利替尼已被批准用于治疗RA。关节周围骨侵蚀在类风湿关节炎的发病机制中起重要作用。然而，尽管JAK抑制(JAKI)的免疫调节作用已被很好地定义，但目前关于JAKI如何影响骨内环境平衡的知识有限。在这里，我们评估了JAK抑制剂tofacitinib和baritinib在稳态条件下或(Ii)雌激素缺乏(卵巢切除)或(Iii)炎症(关节炎)引起的骨丢失小鼠中对骨表型的影响，以评估Jaki对骨代谢的影响是否需要非炎症/炎症挑战。在所有三种模型中，Jaki都增加了骨量，与降低血清中NF-kappa B受体激活剂配体/骨保护素的比率一致。体外观察托法替尼和巴西替尼对破骨细胞和成骨细胞分化的影响。Jaki可显著提高成骨细胞功能(P<；0.05)，但对破骨细胞无直接影响。此外，对暴露于Jaki的成骨细胞进行了mRNA测序和独创性通路分析，结果显示成骨细胞功能的标志物如骨钙素和Wnt信号显著上调。Jaki的合成代谢作用是通过稳定β-连环蛋白来说明的。在类风湿性关节炎患者中，Jaki可诱导骨合成代谢作用，其证据是关节炎骨侵蚀的修复。结果支持Jaki是一种有效的促进成骨细胞功能和骨形成的治疗工具。
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-kappa B 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 beta-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.