Bone resorption induced by parathyroid hormone is strikingly diminished in collagenase-resistant mutant mice
Weiguang Zhao, … , Brendan F. Boyce, Stephen M. Krane
Weiguang Zhao, … , Brendan F. Boyce, Stephen M. Krane
Published February 15, 1999
Citation Information: J Clin Invest. 1999;103(4):517-524. https://doi.org/10.1172/JCI5481.
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Article

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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Figure 1

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Paraffin sections stained with H&E staining of calvarial bone from +...
Paraffin sections stained with H&E staining of calvarial bone from +/+ and r/r mice injected subcutaneously over the hemicalvariae with vehicle or PTH. Shown are representative photomicrographs of sections of calvarial bone that illustrate resorptive responses to PTH of +/+ and r/r mice. Bones from vehicle-injected +/+ mice showed a normal smooth surface of bone marrow spaces and no osteoclasts. Bones from +/+ mice injected with PTH demonstrated marked resorption with increased osteoclasts (arrows) in cavities with irregular surfaces (measured as bone resorption area and illustrated in Fig. 3). In contrast, the appearance of bones from the PTH-treated r/r mice was similar to that of vehicle-treated r/r mice, and few osteoclastic resorption spaces were found. Scale bar, 0.05 mm. H&E, hematoxylin and eosin; PTH, parathyroid hormone.