title: Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids.
abstract: In hyperlipidemia, oxidized lipids accumulate in vascular tissues and trigger atherosclerosis. Such lipids also deposit in bone tissues, where they may promote osteoporosis. We found previously that oxidized lipids attenuate osteogenesis and that parathyroid hormone (PTH) bone anabolism is blunted in hyperlipidemic mice, suggesting that osteoporotic patients with hyperlipidemia may develop resistance to PTH therapy. To determine if oxidized lipids account for this PTH resistance, we blocked lipid oxidation products in hyperlipidemic mice with an ApoA-I mimetic peptide, D-4F, and the bone anabolic response to PTH treatment was assessed. Skeletally immature Ldlr(-/-) mice were placed on a high-fat diet and treated with D-4F peptide and/or with intermittent PTH(1-34) injections. As expected, D-4F attenuated serum lipid oxidation products and tissue lipid deposition induced by the diet. Importantly, D-4F treatment attenuated the adverse effects of dietary hyperlipidemia on PTH anabolism by restoring micro-computed tomographic parameters of bone quality-cortical mineral content, area, and thickness. D-4F significantly reduced serum markers of bone resorption but not bone formation. PTH and D-4F, together but not separately, also promoted bone anabolism in an alternative model of hyperlipidemia, Apoe(-/-) mice. In normolipemic mice, D-4F cotreatment did not further enhance the anabolic effects of PTH, indicating that the mechanism is through its effects on lipids. These findings suggest that oxidized lipids mediate hyperlipidemia-induced PTH resistance in bone through modulation of bone resorption.
authors: Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1679, USA.
authors: Andrew P
authors: AP
authors: Sage
authors: Jinxiu
authors: J
authors: Lu
authors: Elisa
authors: E
authors: Atti
authors: Sotirios
authors: S
authors: Tetradis
authors: Maria-Grazia
authors: MG
authors: Ascenzi
authors: Douglas J
authors: DJ
authors: Adams
authors: Linda L
authors: LL
authors: Demer
authors: Yin
authors: Y
authors: Tintut
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