Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice
Weiguang Zhao, Michael H. Byrne, Brendan F. Boyce, Stephen M. Krane
Weiguang Zhao, Michael H. Byrne, Brendan F. Boyce, Stephen M. Krane
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Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice

Abstract

Parathyroid hormone (PTH) stimulates bone resorption by acting directly on osteoblasts/stromal cells and then indirectly to increase differentiation and function of osteoclasts. PTH acting on osteoblasts/stromal cells increases collagenase gene transcription and synthesis. To assess the role of collagenase 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 cleavage of type I collagen. Human PTH(1–34) was injected subcutaneously over the hemicalvariae in wild-type (+/+) or r/r mice four times daily for three days. Osteoclast numbers, the size of the bone marrow spaces and periosteal proliferation were increased in calvariae from PTH-treated +/+ mice, whereas 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 abundant interstitial collagenase mRNA was detected in the calvarial periosteum of PTH-treated, but not vehicle-treated, r/r and +/+ mice. Calcemic responses, 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 necessary for PTH induction of osteoclastic bone resorption.

Authors

Weiguang Zhao, Michael H. Byrne, Brendan F. Boyce, Stephen M. Krane

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Changes in calvarial bone area and osteoclast number in 4-week-old +/+ a...
Changes in calvarial bone area and osteoclast number in 4-week-old +/+ and r/r mice injected subcutaneously over the hemicalvariae with vehicle (Veh) or PTH. Black bars (means ± SEM) indicate the bone marrow space area (total resorption area), expressed as a percentage of the total bone area in a standard length of calvarial sections. Clear bars (means ± SEM) indicate the number of osteoclasts in the total bone area (i.e., per mm2). The number of mice examined are indicated in parentheses. The bone resorption area and the number of osteoclasts/mm2 were both significantly increased after PTH injection in the +/+ mice (P < 0.005), but not in the r/r mice. In contrast, resorption in response to PTH was markedly reduced, and only occasional osteoclasts were identified in calvarial bone from PTH-treated r/r mice.