Gelsolin deficiency blocks podosome assembly and produces increased bone mass and strength.
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.
Chellaiah
M
M
Renal Division, Department of Medicine, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri 63110, USA.
Kizer
N
N
Silva
M
M
Alvarez
U
U
Kwiatkowski
D
D
Hruska
K A
KA
D000199:Actins / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption; D002113:Calcification, Physiologic / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D018260:Gelsolin / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D006132:Growth Plate / Q000002:abnormalities / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007867:Leg Bones / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015388:Organelles / Q000187:drug effects / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019030:Receptors, Vitronectin / Q000502:physiology; D012795:Sialoglycoproteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013718:Tensile Strength / Q000187:drug effects; D016596:Vinculin / Q000378:metabolism
D000199:Actins; D018260:Gelsolin; D019030:Receptors, Vitronectin; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D016596:Vinculin; D019869:Phosphatidylinositol 3-Kinases