Bone resorption induced by parathyroid hormone is strikingly diminished incollagenase-resistant mutant mice

Parathyroid hormone (PTH) stimulates bone resorption by acting directly on osteoblasts/stromal cells and then indirectly to increase differentiation a nd function of osteoclasts. PTH acting on osteoblasts/stromal cells increas es collagenase gene transcription and synthesis. To assess the role of coll agenase in the bone resorptive actions of PTH, we used mice homozygous (r/r ) for a targeted mutation (r) in Col1a1 that are resistant to collagenase c leavage of type I collagen. Human PTH(1-34) was injected subcutaneously ove r the hemicalvariae in wild-type (+/+) or r/r mice four times daily for thr ee days. Osteoclast numbers, the size of the bone marrow spaces and periost eal proliferation were increased in calvariae from PTH-treated +/+ mice, wh ereas in r/r mice, PTH-induced bone resorption responses were minimal. The r/r mice were not resistant to other skeletal effects of PTH because abunda nt interstitial collagenase mRNA was detected in the calvarial periosteum o f PTH-treated, but not vehicle-treated, r/r and +/+ mice. Calcemic response s, 0.5-10 hours after intraperitoneal injection of PTH, were blunted in r/r mice versus +/+ mice. Thus, collagenase cleavage of type I collagen is nec essary for PTH induction of osteoclastic bone resorption.