Mice lacking beta 3 integrins are osteosclerotic because of dysfunctional osteoclasts

Osteoclasts express the alpha v beta 3 integrin, an adhesion receptor that has been implicated in bone resorption and that is therefore a potential th erapeutic target. To assess the role of this heterodimer in skeletal develo pment in vivo, we engineered mice in which the gene for the beta 3 integrin subunit was deleted. Bone marrow macrophages derived from these mutants di fferentiate in vitro into numerous osteoclasts, thus establishing that alph a v beta 3 is not necessary for osteoclast recruitment. Furthermore, the cl osely related integrin, alpha v beta 5, does not substitute for alpha v bet a 3 during cytokine stimulation or authentic osteoclastogenesis. beta 3 kno ckout mice, but not their heterozygous littermates, develop histologically and radiographically evident osteosclerosis with age. Despite their increas ed bone mass, beta 3-null mice contain 3.5-fold more osteoclasts than do he terozygotes. These mutant osteoclasts are, however, dysfunctional, as evide nced by their reduced ability to resorb whale dentin in vitro and the signi ficant hypocalcemia seen in the knockout mice. The resorptive defect in bet a 3-deficient osteoclasts may reflect absence of matrix-derived intracellul ar signals, since their cytoskeleton is distinctly abnormal and. they fail to spread in vitro, to form actin rings ex vivo, or to form normal ruffled membranes in vivo. Thus, although it is not required for osteoclastogenesis , the integrin alpha v beta 3 is essential for normal osteoclast function.