title: Role of paraoxonase-1 in bone anabolic effects of parathyroid hormone in hyperlipidemic mice.
abstract: Hyperlipidemia blunts anabolic effects of intermittent parathyroid hormone (PTH) on cortical bone, and the responsiveness to PTH are restored in part by oral administration of the antioxidant ApoA-I mimetic peptide, D-4F. To evaluate the mechanism of this rescue, hyperlipidemic mice overexpressing the high-density lipoprotein-associated antioxidant enzyme, paraoxonase 1 (Ldlr(-/-)PON1(tg)) were generated, and daily PTH injections were administered to Ldlr(-/-)PON1(tg) and to littermate Ldlr(-/-) mice. Expression of bone regulatory genes was determined by realtime RT-qPCR, and cortical bone parameters of the femoral bones by micro-computed tomographic analyses. PTH-treated Ldlr(-/-)PON1(tg) mice had significantly greater expression of PTH receptor (PTH1R), activating transcription factor-4 (ATF4), and osteoprotegerin (OPG) in femoral cortical bone, as well as significantly greater cortical bone mineral content, thickness, and area in femoral diaphyses compared with untreated Ldlr(-/-)PON1(tg) mice. In contrast, in control mice (Ldlr(-/-)) without PON1 overexpression, PTH treatment did not induce these markers. Calvarial bone of PTH-treated Ldlr(-/-)PON1(tg) mice also had significantly greater expression of osteoblastic differentiation marker genes as well as BMP-2-target and Wnt-target genes. Untreated Ldlr(-/-)PON1(tg) mice had significantly greater expression of PTHR1 than untreated Ldlr(-/-) mice, whereas sclerostin expression was reduced. In femoral cortical bones, expression levels of transcription factors, FoxO1 and ATF4, were also elevated in the untreated, control Ldlr(-/-)PON1(tg) mice, suggesting enhancement of cellular protection against oxidants. These findings suggest that PON1 restores responsiveness to PTH through effects on oxidant stress, PTH receptor expression, and/or Wnt signaling.
authors.affiliation: Department of Physiology, University of California, Los Angeles, CA 90095-1679, United States.
authors.forename: Jinxiu
authors.initials: J
authors.lastname: Lu
authors.forename: Henry
authors.initials: H
authors.lastname: Cheng
authors.forename: Elisa
authors.initials: E
authors.lastname: Atti
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.forename: Linda L
authors.initials: LL
authors.lastname: Demer
authors.forename: Yin
authors.initials: Y
authors.lastname: Tintut
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage*; D000818:Animals; D043303:Aryldialkylphosphatase / Q000502:physiology*; D001842:Bone and Bones / Q000187:drug effects* / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000201:enzymology*; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010281:Parathyroid Hormone / Q000008:administration & dosage*; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D045930:Anabolic Agents; D008055:Lipids; D010281:Parathyroid Hormone; D011973:Receptors, LDL; D043303:Aryldialkylphosphatase