Interstitial Collagenase Activity Stimulates the Formation of Actin Rings and Ruffled Membranes in Mouse Marrow Osteoclasts

Interstitial collagenase activity stimulates bone resorption by mouse marrow osteoclasts (1). Here, we show that collagenase activity promotes bone re- sorption by activating adherent osteoclasts to resorb bone. Inhibition of interstitial collagenase activity, ei- ther with peptidomimetic hydroxymates or with a spe- cific anti-interstitial collagenase inhibiting antibody, reduced bone resorption by 73-92%. Equal numbers of osteoclasts adhered to bone in the presence of collage- nase inhibitors and osteoclast survival was unaffected. In contrast, formation of actin rings and polarization of the vacuolar-H + -ATPase (V-ATPase) to ruffled mem- branes, two indicators of osteoclast activation, were decreased by inhibiting collagenase activity and stimu- lated in the presence of cleaved or heat-denatured type I collagen in proportion to increases and decreases of bone resorptive activity. Addition of excess recombinant osteoprotegerin-ligand to cultures did not restore bone resorption in the presence of interstitial collagenase in- hibitors. These data support the hypothesis that cleaved collagen stimulates osteoclastic bone resorption by trig- gering cytoskeletal reorganization and transport of V- ATPase from cytoplasmic stores to ruffled membranes.