The regulation of cartilage resorption is important both in cartilage pathophysiology and angiogenesis. Previous work has identified a link between calcification and activation of collagenolysis. The aim here was to test whether production of collagenase itself is also calcification-dependent, using a high-density growth plate chondrocyte culture model of calcification. Ultrastructural studies indicated that calcification occurred around large hypertrophic cells. There was no indication of phagocytosis of crystals even by cells lying next to mineral aggregates, although remodeling of the organic matrix by cell processes was evident. Release of collagenase activity increased dramatically between 24 and 48 h postcalcification, from low or undetectable basal levels. In contrast, gelatinase production was not calcification-dependent. Collagenase was released almost entirely in the latent form, being a consequence of increased protein synthesis rather than activation of existing enzyme. This linkage of calcification with latent collagenase production represents part of a coordinated remodeling of both collagenous and mineral components of the matrix which may also extend, in vivo, to the control of microvascular invasion and resorption.