Osteoclasts, the multinucleated cells responsible for the degradation of mineralized matrices, are thought to resorb bone by a common mechanism, despite differences in bone matrix composition. However, certain bone diseases, in which defects in resorption occur at specific sites, such as craniometaphyseal dysplasia, raise the possibility that the mechanism of osteoclastic resorption may itself be site-specific. Cysteine proteinases (CPs), particularly cathepsin K, are essential for bone resorption, whereas matrix metalloproteinases (MMPs) are involved in resorption in calvarial tissue explants, but not in resorption by isolated osteoclasts. Since the latter usually involves the use of osteoclasts isolated from long bones, it is possible that resorption by osteoclasts from different sites may utilize different proteinases. To investigate whether osteoclasts from calvarial and long bones differ in their resorptive mechanism and, if so, whether these differences are related to the substratum that they resorb.