Antibody to beta(3) integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat

The cell surface integrin, alpha(v) beta(3), is important for the attachment of osteoclasts to bone matrix and the subsequent resorption of bone. The present study was designed to determine the effects of F11, a monoclonal antibody to the rat beta(3) subunit, on calcium mobilization in a rat model of bone resorption. Male Sprague Dawley rats became hypocalcemic within 18 h after thyroparathyroidectomy. Synthetic PTH-related protein (PTHrP((1-34))) administered to control rats caused serum calcium to return to normal. Anti-beta(3) treatment of rats after thyroparathyroidectomy inhibited the calcemic response to PTHrP by 65%. Circulating F11 was biologically active as demonstrated by osteoclast retraction and by the inhibition of adenosine diphosphate-induced platelet aggregation via inhibition of the platelet integrin alpha(IIb)beta(3) in ex vivo assays. F11 antibody was localized by immunohistological staining to osteoclasts in long bones, suggesting that the mechanism of action of the antibody was via a direct effect upon osteoclasts. Echistatin and calcitonin also inhibited calcemic responses to PTHrP in this in vivo model, whereas an isotype-matched, control antibody was ineffective. These studies provide the first direct evidence in vivo that osteoclast-mediated bone resorption is regulated via a beta(3) integrin.