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PMID: 10684249 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of cell biology ·Vol. 148 ·No. 4 ·2000-02-21 ·Pages 665-78

Chellaiah M, Kizer N, Silva M, Alvarez U, Kwiatkowski D, Hruska KA

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 alpha(v)beta(3) 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 alpha(v)beta(3)-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 alpha(v)beta(3) integrin.

MeSH Terms
Actins/metabolism Animals Bone Resorption Calcification, Physiologic/drug effects Cell Movement/drug effects Cells, Cultured Cytoskeleton/drug effects,metabolism Gelsolin/analysis,deficiency,genetics,physiology Gene Deletion Growth Plate/abnormalities,cytology,drug effects,metabolism Leg Bones/cytology,drug effects,growth & development,metabolism Mice Mice, Knockout Organelles/drug effects,metabolism Osteoclasts/cytology,drug effects,enzymology,metabolism Osteopontin Phosphatidylinositol 3-Kinases/chemistry,metabolism Phosphorylation/drug effects Receptors, Vitronectin/physiology Sialoglycoproteins/pharmacology Signal Transduction/drug effects Tensile Strength/drug effects Vinculin/metabolism
Chemicals
Actins Gelsolin Receptors, Vitronectin Sialoglycoproteins Spp1 protein, mouse Osteopontin Vinculin Phosphatidylinositol 3-Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Chellaiah M
Renal Division, Department of Medicine, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri 63110, USA.
Kizer N
Silva M
Alvarez U
Kwiatkowski D
Hruska K A
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.148.4.665
Published
2000-02-21
Pages
665-78
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2169374
Subset
IM
Grants
NIAMS NIH HHS · AR41677 · United States
External Links
PubMed source DOI: 10.1083/jcb.148.4.665 PMC Full Text View journal details
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