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 À/À 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 À/À 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. ß

Skeletal inflammation and attenuation of Wnt signaling, Wnt ligand expression, and bone formation in atherosclerotic ApoE-null mice

“…Consistent with the evidence for a linkage between atherosclerosis and osteoporosis in humans, ApoE-null (ApoE-KO) mice or LDL receptor-null mice fed a HFD exhibit reduced bone mass (24,48,49,53). The mass and structural integrity of the skeleton are maintained by teams of osteoclasts and osteoblasts that, respectively, resorb old bone and replace it with new (38).…”

“…ports in both ApoE-KO and LDL receptor-null mice (24,48,49,53). However, in the earlier studies, the HFD was begun at ϳ1 to ϳ3 mo of age, when growth and bone formation are high (18).…”

17-β-estradiol up-regulates apolipoprotein genes expression during osteoblast differentiation <i>in vitro </i>

“…The ApoA-I mimetic peptide, D-4F, reduced serum markers of bone resorption in mice (39). Decreased bone mineral density was noted in subjects carrying familial defective ApoB-100 (40).…”

Serum Lipids Effect on Bone Mineral Density: A Pilot Study in Apparently Healthy Syrians

“…They were also found to affect bone resorption by increasing osteoclastogenesis cytokines production such as receptor activator of nuclear factor-κB (RANKL) and interleukin-6 from both T-lymphocytes and osteoblasts [17][18][19][20][21]. Furthermore, it has been reported that oxidized lipids down regulate parathyroid hormone receptor (PTH1R) in osteoblasts causing resistance to PTH [22][23][24][25][26].…”