Vinculin regulates osteoclast function

Tomohiro Fukunaga, Wei Zou, Julia T. Warren, Steven L. Teitelbaum

研究成果: Article査読

27 被引用数 (Scopus)

抄録

Osteoclastic bone resorption depends upon the cell's ability to organize its cytoskeleton. Because vinculin (VCL) is an actinbinding protein, we asked whether it participates in skeletal degradation. Thus, we mated VCL fl/fl mice with those expressing cathepsin K-Cre (CtsK-VCL) to delete the gene in mature osteoclasts or lysozyme M-Cre (LysM-VCL) to target all osteoclast lineage cells. VCL-deficient osteoclasts differentiate normally but, reflecting cytoskeletal disorganization, form small actin rings and fail to effectively resorb bone. In keeping with inhibited resorptive function, CtsK-VCL and LysM-VCL mice exhibit a doubling of bone mass. Despite cytoskeletal disorganization, the capacity of VCL-/- osteoclastic cells to normally phosphorylate c-Src in response to αvβ3 integrin ligand is intact. Thus, integrin-Activated signals are unrelated to the means by which VCL organizes the osteoclast cytoskeleton. WT VCL completely rescues actin ring formation and bone resorption, as does VCLP878A, which is incapable of interacting with Arp2/3. As expected, deletion of the VCL tail domain (VCL1-880), which binds actin, does not normalizeVCL-/- osteoclasts. The same is true regarding VCLI997A, which also prevents VCL/actin binding, and VCLA50I and VCL811-1066, both of which arrest talin association. Thus, VCL binding talin, but not Arp2/3, is critical for osteoclast function, and its selective inhibition retards physiological bone loss.

本文言語English
ページ(範囲)13554-13564
ページ数11
ジャーナルJournal of Biological Chemistry
289
19
DOI
出版ステータスPublished - 2014
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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