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 pathways of bone collagen degradation in the enhanced bone resorption induced by PTH and to determine if interfering with collagen resorption affects the anabolic actions of PTH on collagen deposition and bone formation. We will use a model in the mouse in which a mutation has been targeted to the Colla-I gene that encodes amino acid substitutions in the a1(I) chains that result in resistance of native type I collagen to cleavage in the helical domain by collagenase. We have evidence that the murine collagenase, the homologue of human collagenase-3 (MMP-13), makes an additional cleavage in the amino (N) telopeptide of type I collagen which could also function in PTH-induced bone resorption.
Specific Aim I : Assess osteoclast-mediated bone resorption and other aspects of bone remodeling in vivo in heterozygous and homozygous collagenase-resistant (r/r) mice compared to wild type mice. Efforts will be directed towards establishing the mechanisms of the decreased responses of the r/r mice to the effects of PTH in stimulation of bone resorption. Effects of PTH will be compared to those of other inducers of bone resorption such as interleukin-1(IL-1) or estrogen withdrawal (oophorectomy).
Specific Aim II : Analyze the effects of PTH and IL-1 on bone resorption in vitro on calvaria from r/r and +/+ newborn mice. Preliminary data indicate a decrease in PTH-induced osteoclastic bone resorption; we will utilize the in vitro system to determine what cellular interactions and/or soluble factors (e.g. collagen degradation products, ligands released from the matrix), mediate the effects of PTH observed.
Aim III : Assess the effects of low-dose, systemic, PTH administered intermittently, on bone formation in vivo using histomorphometry and DEX measurements of bone mass in r/r compared to +/+ mice. The proposed studies should enable us to determine whether the anabolic effects of PTH in the rodents are dependent upon the catabolic effects of PTH when collagenase cleavage at the helical site in type I collagen is blocked.
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