Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR.
Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR.
复制标题
通过靶向软骨细胞 CaSR 预防啮齿类颞下颌关节损伤诱发的骨关节炎
DOI：
10.1002/jbmr.3643
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发表时间：
2018
影响因子：
6.2
通讯作者：
Meiqing Wang
中科院分区：
文献类型：
--
作者：
Mian Zhang;Hongxu Yang;Xianghong Wan;Lei Lu;Jing Zhang;Hongyun Zhang;Tao Ye;Qian Liu;Mianjiao Xie;Xiaodong Liu;Shibin Yu;Shaoxiong Guo;Wenhan Chang;Meiqing Wang
创伤性关节损伤产生骨关节炎软骨，通过未知的细胞和分子机制表现出加速的软骨细胞终末分化和基质降解。在这里，我们报告了生物力学应力增加钙敏感受体（CaSR）表达的能力，这是软骨细胞终末分化的关键驱动因素，在培养的软骨细胞中受到流体流动剪切应力（FFSS）和在啮齿动物颞下颌关节（TMJ）软骨的软骨细胞中受到单侧前牙反咬（UAC）。在培养的ATDC 5细胞或TMJ软骨细胞中，FFSS诱导Ca2+负荷和CaSR在内质网（ER）中的定位，偶然地加速细胞分化，这可以通过清空ER Ca2+储存或CaSR敲低而被废除。同样，急性软骨细胞特异性Casr敲除（KO）可防止UAC诱导的小鼠TMJ软骨中软骨细胞终末分化和基质降解的加速。更重要的是，局部注射CaSR拮抗剂NPS2143复制了Casr KO在预防UAC治疗大鼠TMJ软骨中骨关节炎表型发展方面的作用。我们的研究揭示了一种新的病理作用的钙SR在骨关节炎软骨的发展，由于异常的机械刺激，并支持calcilytics在预防骨关节炎的治疗潜力，在颞下颌关节靶向的钙SR。© 2018美国骨与矿物质研究学会。
Traumatic joint injuries produce osteoarthritic cartilage manifesting accelerated chondrocyte terminal differentiation and matrix degradation via unknown cellular and molecular mechanisms. Here we report the ability of biomechanical stress to increase expression of the calcium‐sensing receptor (CaSR), a pivotal driver of chondrocyte terminal differentiation, in cultured chondrogenic cells subjected to fluid flow shear stress (FFSS) and in chondrocytes of rodent temporomandibular joint (TMJ) cartilage subjected to unilateral anterior cross‐bite (UAC). In cultured ATDC5 cells or TMJ chondrocytes, FFSS induced Ca2+loading and CaSR localization in endoplasmic reticulum (ER), casually accelerating cell differentiation that could be abrogated by emptying ER Ca2+stores or CaSR knockdown. Likewise, acute chondrocyte‐specific Casr knockout (KO) prevented the UAC‐induced acceleration of chondrocyte terminal differentiation and matrix degradation in TMJ cartilage in mice. More importantly, local injections of CaSR antagonist, NPS2143, replicated the effects of Casr KO in preventing the development of osteoarthritic phenotypes in TMJ cartilage of the UAC‐treated rats. Our study revealed a novel pathological action of CaSR in development of osteoarthritic cartilage due to aberrant mechanical stimuli and supports a therapeutic potential of calcilytics in preventing osteoarthritis in temporomandibular joints by targeting the CaSR. © 2018 American Society for Bone and Mineral Research.