(Taken from the application): Parathyroid hormone (PTH) can induce bone resorption by acting directly on osteoblasts and stromal cells and then indirectly to increase the differentiation and function of osteoclasts. Bone resorption involves removal of the mineral as well as the organic phase (90-95% type I collagen). The goals of this project are to clarify the roles of the matrix metalloproteinase (MMP)- collagenases in the enhanced bone resorption induced by PTH and to determine how these effects of PTH on MMP expression and action relate to the anabolic effects of PTH on bone formation. We will use two mouse models: 1. Mice in which a mutation has been targeted to Col1a1 that encodes amino acid substitutions in the alpha1(I) chain of type I collagen that result in resistance(r) to collagenase cleavage; 2. Mice in which we introduced a null mutation into the MMP-13 (collagenase-3) gene that results in deletion of the function of this gene. We have shown that r/r mice have a decreased osteoclastic resorptive response to PTH, and spontaneously develop increased bone deposition. This is accompanied, perhaps paradoxically, by osteocyte loss and osteocyte and osteoblast apoptosis. Understanding the role of collagenases in normal bone remodeling and determining whether stimulation of bone formation by PTH is dependent on bone resorption using the r/r mice as well as mice with the null mutation we engineered in the MMP-13 gene should help in the development of methods for optimizing the use of PTH in diseases such as osteoporosis. Thus, our Specific Aims are as follows:
Specific Aim I. Define mechanisms of altered generation/activation of osteoclasts by PTH in mice (r/r) with a targeted resistance (r) to cleavage of type collagen.
Specific Aim II. Determine mechanisms of increased bone cell apoptosis observed in vivo in the r/r mice.
Specific Aim III. Define the mechanisms of increased activation of bone surfaces and increased bone deposition in r/r mice.
Specific Aim I V. The phenotype of the r/r mice is presumably due to resistance to degradation of type I collagen by collagenase. Determine which collagenase among the MMPs is responsible for the phenotype of MMP-8, MMP-13, MMP-14? Since we have been successful in introducing a functional null mutation in the gene encoding MMP-13, we will start by examining the effects of PTH, as described for the r/r mice, in the MMP-13 -/- mice.
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