Rab34 plays a critical role as a bidirectional regulator of osteoclastogenesis
Rab34 plays a critical role as a bidirectional regulator of osteoclastogenesis
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DOI：
10.1002/cbf.3691
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发表时间：
2022-03
影响因子：
3.6
通讯作者：
Yunxia Feng;M. T. Tran;Yanyin Lu;Kaung Htike;Yuka Okusha;C. Sogawa;T. Eguchi;T. Kadowaki;E. Sakai;T. Tsukuba;K. Okamoto
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文献类型：
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作者：
Yunxia Feng;M. T. Tran;Yanyin Lu;Kaung Htike;Yuka Okusha;C. Sogawa;T. Eguchi;T. Kadowaki;E. Sakai;T. Tsukuba;K. Okamoto
越来越多的证据表明，Rab GTP酶代表Ras超家族的最大分支，最近成为通过调节特定亚细胞区室之间的囊泡运输来调节破骨细胞生成的核心因子。其中，Rab 34 GTdR已被确定为对高尔基体后分泌途径和吞噬作用很重要;然而，其在破骨细胞生成中的具体作用完全不清楚。在这里，在来自鼠巨噬细胞如RAW‐D细胞或骨髓源性巨噬细胞的破骨细胞形成的体外模型中，我们揭示Rab 34双向调节破骨细胞生成。更具体地说，Rab 34作为破骨细胞分化的负调节因子，通过早期内体-晚期内体-溶酶体轴促进溶酶体诱导的两种破骨细胞生成表面受体c-fms和RANK的蛋白水解，从而减轻破骨细胞分化的两种主要调节因子c-fos和NFATc-1的转录活性，最终减弱破骨细胞分化和骨吸收。此外，Rab 34在调节溶酶体相关蛋白酶（包括基质金属蛋白酶9和组织蛋白酶K）穿过破骨细胞皱褶边界的分泌网络中起着至关重要的作用，有助于调节骨吸收。
Accumulating evidence suggests that Rab GTPases representing the largest branch of Ras superfamily have recently emerged as the core factors for the regulation of osteoclastogenesis through modulating vesicular transport amongst specific subcellular compartments. Among these, Rab34 GTPase has been identified to be important for the post‐Golgi secretory pathway and for phagocytosis; nevertheless, its specific role in osteoclastogenesis has been completely obscure. Here, upon the in vitro model of osteoclast formation derived from murine macrophages like RAW‐D cells or bone marrow–derived macrophages, we reveal that Rab34 regulates osteoclastogenesis bidirectionally. More specifically, Rab34 serves as a negative regulator of osteoclast differentiation by promoting the lysosome‐induced proteolysis of two osteoclastogenic surface receptors, c‐fms and RANK, via the axis of early endosomes‐late endosomes–lysosomes, leading to alleviate the transcriptional activity of two of the master regulator of osteoclast differentiation, c‐fos and NFATc‐1, eventually attenuating osteoclast differentiation and bone resorption. Besides, Rab34 plays a crucial role in modulating the secretory network of lysosome‐related proteases including matrix metalloprotease 9 and Cathepsin K across the ruffled borders of osteoclasts, contributing to the regulation of bone resorption.