Gelsolin deficiency blocks podosome assembly and produces increased bone mass and strength

Meenakshi Chellaiah, Neil Kizer, Matthew Silva, Ulises Alvarez, David Kwiatkowski, Keith A. Hruska

Research output: Contribution to journalArticlepeer-review

197 Scopus citations

Abstract

Osteoclasts are unique cells that utilize podosomes instead of focal adhesions for matrix attachment and cytoskeletal remodeling during motility. We have shown that osteopontin (OP) binding to the α(v)β3 integrin of osteoclast podosomes stimulated cytoskeletal reorganization and bone resorption by activating a heteromultimeric signaling complex that includes gelsolin, pp(60c-src), and phosphatidylinositol 3'-kinase. Here we demonstrate that gelsolin deficiency blocks podosome assembly and α(v)β3-stimulated signaling related to motility in gelsolin-null mice. Gelsolin-deficient osteoclasts were hypomotile due to retarded remodeling of the actin cytoskeleton. They failed to respond to the autocrine factor, OP, with stimulation of motility and bone resorption. Gelsolin deficiency was associated with normal skeletal development and endochondral bone growth. However, gelsolin-null mice had mildly abnormal epiphyseal structure, retained cartilage proteoglycans in metaphyseal trabeculae, and increased trabecular thickness. With age, the gelsolin-deficient mice expressed increased trabecular and cortical bone thickness producing mechanically stronger bones. These observations demonstrate the critical role of gelsolin in podosome assembly, rapid cell movements, and signal transduction through the α(v)β3 integrin.

Original languageEnglish
Pages (from-to)665-678
Number of pages14
JournalJournal of Cell Biology
Volume148
Issue number4
DOIs
StatePublished - Feb 21 2000

Keywords

  • Actin
  • Gelsolin
  • Osteoclasts
  • Phosphatidylinositol 3'-kinase
  • Podosomes

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