Rab34 plays a critical role as a bidirectional regulator of osteoclastogenesis. (14th March 2022)

• Record Type: Journal Article
• Authors: Feng, Yunxia; Tran, Manh Tien; Lu, Yanyin; Htike, Kaung; Okusha, Yuka; Sogawa, Chiharu; Eguchi, Takanori; Kadowaki, Tomoko; Sakai, Eiko; Tsukuba, Takayuki; Okamoto, Kuniaki
• Is Part Of: Cell biochemistry and function. Volume 40:Number 3(2022)
• Page Start: 263
• Page End: 277
• Publication Date: 2022-03-14
• Subjects: c‐fms -- NFATc‐1 -- osteoclasts -- Rab34 -- RANK -- vesicular transport; Cytochemistry -- Periodicals; Cell metabolism -- Periodicals; Biochemistry -- Periodicals; Cytology -- Periodicals; 572
• DOI: 10.1002/cbf.3691
• Languages: English
• ISSNs: 0263-6484

Abstract

Abstract: 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. Significance statement: Rab GTPases have emerged as the spatiotemporal regulators of intracellular vesicular transport. Molecular mechanisms illuminating the specific roles of Rab34 in regulating osteoclastogenesis remain elusive. In our current study, Rab34 has been substantiated as a regulatory intermediator of osteoclastogenesis via (1) modulating the abundance of cell surface receptors, c‐fms and RANK receptors, and (2) directing the lysosome movement to ruffled borders of osteoclasts for the secretion of lysosomal proteases including metalloprotease 9 and Cathepsin K. This study has further provided new insights into the regulatory roles of osteoclastogenesis via functional interrelated cooperation of Rab GTPases, at least Rab34, and lysosomes to direct process of bone resorption.