Age-related bone loss is due in part to a decrease in osteoblast number. During the previous funding period? it was found that activation of PPARy caused bone loss by stimulating the development of adipocytes at the? expense of osteoblasts from their common multipotential mesenchymal stem cell progenitor, and by? increasing the apoptosis of preosteoblasts. Oxidized lipid ligands of PPARy are generated by the actions of? reactive oxygen species (ROS) and/or 12,15-lipoxygenase (Alox15) on linoleic and arachidonic acid.? Increased Alox15 expression has been associated with decreased bone mass and strength, and evidence? leading to the development of this application revealed an increase in the level of oxidized lipids in murine? bone between 8 and 31 months of age. These changes were associated with loss of bone mass and? strength, decreased bone formation rate, increased osteoblast and osteocyte apoptosis, and elevated levels? of PPARy and Alox15. Reversal of age-related bone loss has been achieved by daily administration of? parathyroid hormone (PTH), but the efficacy of this therapy is variable for unknown reasons. In view of? evidence that the anabolic effect of PTH is due at least in part to attenuation of osteoblast apoptosis, PTH? may reverse the increased osteoblast apoptosis seen in aged mice. The hormone may also increase? osteoblast production by inhibiting PPARy activity. The above observations form the basis of the hypothesis? that PPARy is increasingly activated by oxidized lipids with advancing age, secondary to elevated levels of? ROS and Alox15. Hence, age-related bone loss is due, at least in part, to increased adipogenesis at the? expense of osteoblastogenesis and increased apoptosis of osteoblast progenitors. As a corollary, PTH is a? rational and especially efficacious treatment for age-related osteoporosis because it counteracts the PPARymediated? adverse effects of oxidized lipids and ROS on bone. To test this hypothesis, the role of oxidized? lipids generated by Alox15 in age-related bone loss will be examined in vivo by pharmacologic and genetic? manipulation of the enzyme and subsequent measurement of bone mass, architecture, strength, osteoblast? apoptosis, and bone formation rate (Aim 1). In addition, in vitro studies will be done to distinguish between? PPARy-dependent and PPARy-independent effects of Alox15-derived oxidized lipids on osteoblast? progenitors (Aim 2). Finally, studies will be performed to investigate whether intermittent administration of? PTH to aged mice will specifically reverse the negative skeletal effects of increased oxidized lipids and ROS? and thereby increase bone mass (Aim 3). This work should advance knowledge of how the elderly develop? osteoporosis and bone fractures. Furthermore, it should provide a better understanding of how to optimize? the treatment of this condition.?
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