Vitamin D receptor activated by vitamin D administration alleviates Mycobacterium tuberculosis-induced bone destruction by inhibiting NFκB-mediated aberrant osteoclastogenesis
Vitamin D receptor activated by vitamin D administration alleviates Mycobacterium tuberculosis-induced bone destruction by inhibiting NFκB-mediated aberrant osteoclastogenesis
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DOI：
10.1096/fj.202100135r
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发表时间：
2021-06-01
期刊：
影响因子：
4.8
通讯作者：
Zhang，Zehua
中科院分区：
文献类型：
--
作者：
Deng，Jiezhong;Yang，Yusheng;Zhang，Zehua
临床上，结核分枝杆菌引起的骨破坏严重，尤其是在维生素D（VD）缺乏的患者中。VD在M.结核病引起的骨质破坏仍然清楚在此背景下，我们研究了VD和维生素D受体（VDR）在M。结核病导致的骨质破坏首先，我们用牛分枝杆菌、卡介苗（M. bovisBCG）。然后，我们通过VD给药激活VDR。进行TRAP和FAK染色、骨吸收测定、免疫荧光染色、qPCR和蛋白质印迹。在体内，M.建立结核病诱导的小鼠颅骨溶骨性模型，进行μCT和组织学分析。我们发现VDR和TRAP在骨结核组织中表达上调，证明M.结核感染促进RAW 264.7和BBM的破骨细胞生成。VD可剂量依赖性地抑制破骨细胞分化、融合和骨吸收。而当VDR被敲低后，VD对破骨细胞的抑制作用消失。在机制上，VDR的激活抑制了IκB α的磷酸化，从而抑制了NFκB信号通路，减轻了破骨细胞的生成。此外，在颅骨骨质溶解模型中，VD给药减少了骨质溶解，但在VDR−/−小鼠中没有。我们的研究首次证明了VD给药激活VDR可抑制M。结核病导致的骨质破坏我们的结果表明VD和VDR是M潜在的治疗靶点。结核病引起的骨破坏，并为新的治疗策略的发展具有重要的临床意义。
Clinically, bone destruction caused byMycobacterium tuberculosiswas serious especially in patients with vitamin D (VD) deficiency. However, the role of VD inM. tuberculosis‐induced bone destruction remains clear. In this context, we investigate the role of VD and vitamin D receptor (VDR) in theM. tuberculosis‐induced bone destruction. First, we infected RAW264.7 and bone marrow‐derived macrophages (BMMs) withMycobacterium bovisBacillus Calmette‐Guérin (M. bovisBCG) in vitro. Then, we activated VDR through VD administration. TRAP and FAK staining, bone resorption assays, immunofluorescence staining, qPCR, and western blot were carried out. In vivo, theM. tuberculosis‐induced osteolytic model on the murine skull was established and the μCT and histological analyses were performed. We found that VDR and TRAP were upregulated in bone tuberculosis tissue and proved thatM. tuberculosisinfection promoted osteoclastogenesis in RAW264.7 and BMMs. VD could inhibit osteoclasts differentiation, fusion, and bone resorption dose‐dependently. However, when VDR was knocked down, the inhibitory effect of VD on osteoclasts disappeared. In mechanism, activation of VDR inhibits the phosphorylation of IκB α, thereby inhibiting NFκB signaling pathway and alleviating osteoclastogenesis. Furthermore, in the skull osteolysis model, VD administration reduced osteolysis, but not in VDR−/−mice. Our study, for the first time, demonstrates that activation of VDR by VD administration inhibitsM. tuberculosis‐induced bone destruction. Our results reveal that VD and VDR are potential therapeutic targets forM. tuberculosis‐induced bone destruction, and are of great clinical significance for the development of new therapeutic strategies.