OXIDIZED LIPIDS, AGE-RELATED BONE LOSS AND ITS REVERSAL BY INTERMITTENT PTH

Univ Of Arkansas For Med Scis, Little Rock AR

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Abstract

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