Vinculin regulates osteoclast function

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

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)13554-13564
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number19
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Fukunaga, T., Zou, W., Warren, J. T., & Teitelbaum, S. L. (2014). Vinculin regulates osteoclast function. Journal of Biological Chemistry, 289(19), 13554-13564. https://doi.org/10.1074/jbc.M114.550731