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© The Rockefeller University Press, 0021-9525/2000/2/665/ $5.00
The Journal of Cell Biology, Volume 148, Number 4, February 21, 2000 665-678

Original Article

Gelsolin Deficiency Blocks Podosome Assembly and Produces Increased Bone Mass and Strength

Meenakshi Chellaiaha, Neil Kizera, Matthew Silvab, Ulises Alvareza, David Kwiatkowskid, and Keith A. Hruskaa,c
a Renal Division, Department of Medicine, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri 63110
b Department of Orthopaedics, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri 63110
c Department of Cell Biology, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri 63110
d Division of Preventive Medicine, Department of Medicine, Peter Brent Brigham Hospital, Harvard University, Boston, Massachusetts 02115

Correspondence to: Keith A. Hruska, Renal Division, Barnes Jewish Hospital North, Washington University, 216 South Kingshighway, St. Louis, MO 63110. Tel:(314) 454-7771 Fax:(314) 454-5126 E-mail:khruska{at}imgate.wustl.edu.

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}vß3 integrin of osteoclast podosomes stimulated cytoskeletal reorganization and bone resorption by activating a heteromultimeric signaling complex that includes gelsolin, pp60c-src, and phosphatidylinositol 3'-kinase. Here we demonstrate that gelsolin deficiency blocks podosome assembly and {alpha}vß3-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}vß3 integrin.

Key Words: gelsolin, phosphatidylinositol 3'-kinase, actin, podosomes, osteoclasts


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