To achieve the long sought therapeutic goal of rebuilding bone in osteopenic states, osteoblast number must be increased by stimulating their differentiation from local progenitors and/or extending osteoblast life span. We recently obtained evidence that the increased osteoblast number, bone formation rate, and bone mass caused by intermittent administration of parathyroid hormone (PTH) to mice is due to an anti- apoptotic effect of the hormone on osteoblast. Moreover, the contribution of increased osteoblast or lining cell activation-previously proposed to mediate the anabolic effect of PTH- was minimal if any. In vitro studies indicated that PTH inhibited the apoptosis of osteoblastic cells induced by etoposide via cAMP-mediated intracellular signaling events, and the PTH inhibited osteoblast apoptosis caused by loss of integrin signaling events; and that PTH inhibited osteoblast apoptosis caused by loss of integrin signaling, i.e. anoikis. We propose the hypothesis that the anabolic effect of PTH on the skeleton due to a reduction in the prevalence of osteoblast apoptosis; and that this effect is mediated by inhibition of the osteoblast anoikis that occurs during bone formation. To dissect the relative contribution of osteoblast apoptosis prevention, increased osteoblast differentiation, and lining cell activation, to the anabolic effect of PTH, we will use OG2-Hsv-tk transgenic mice in which the number of osteoblast progenitors and osteoblasts can be controlled with ganciclovir. The molecular mechanism by which PTH inhibits osteoblast apoptosis will be studied by focusing on PTH-stimulated processes that have the potential of replacing anti-apoptotic signals that are lost during anoikis. The include cAMP-dependent intracellular signaling pathways; the generation of new integrin-binding molecules via pericellular matrix degradation by matrix metalloproteinases; and the production of anti- apoptotic growth factors including IL-6 type cytokines and insulin-like growth factors. The results of this work will set the stage for approaching the long-term goal of determining the in vivo relevance of critical PTH- induced anti-apoptotic pathways for stimulation of bone formation, and elucidating the role of anoikis in determining osteoblast life span, using appropriate transgenic mice.
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