title: Hyperlipidemia impairs osteoanabolic effects of PTH.
abstract: Epidemiological and in vitro studies have suggested that hyperlipidemia/oxidized phospholipids adversely affect bone. We recently found that oxidized phospholipids attenuate PTH-induced cAMP and immediate-early gene (IEG) expression in MC3T3-E1 cells, raising concerns that clinical hyperlipidemia may attenuate osteoanabolic effects of PTH in vivo. Thus, we studied whether intermittent PTH treatment has differential osteoanabolic effects in wildtype (C57BL/6) and hyperlipidemic (LDLR(-/-)) mice. Consistent with our previous in vitro studies, induction of IEGs in calvarial tissue, 45 min after a single dose of recombinant hPTH(1-34), was attenuated in LDLR(-/-) mice compared with C57BL/6 mice. Daily hPTH(1-34) injections for 5 wk significantly increased total and cortical BMD and BMC, assessed by pQCT, in C57BL/6 mice. However, this induction was completely abrogated in LDLR(-/-) mice. Similarly, PTH(1-34) failed to increase BMD in another hyperlipidemic mouse model, ApoE(-/-) mice. Histomorphometric analysis showed that trabecular bone of both mice responded similarly to PTH(1-34). Structural parameters improved significantly in response to PTH(1-34) in both mouse strains, although to a lesser degree in LDLR(-/-) mice. With PTH(1-34) treatment, osteoblast surface trended toward an increase in C57BL/6 mice and increased significantly in LDLR(-/-) mice. PTH(1-34) did not alter resorption parameters significantly, except for the eroded surface (ES/BS), which was reduced in the C57BL/6 but not in the LDLR(-/-) mice. These results show that PTH(1-34) has adverse effects on cortical bones of the hyperlipidemic mice, suggesting that the therapeutic effects of PTH may be compromised in the presence of hyperlipidemia.
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1679, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Huang
authors.forename: Jinxiu
authors.initials: J
authors.lastname: Lu
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Ivanov
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Sage
authors.forename: Wendy
authors.initials: W
authors.lastname: Tseng
authors.forename: Linda L
authors.initials: LL
authors.lastname: Demer
authors.forename: Yin
authors.initials: Y
authors.lastname: Tintut
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000503:physiopathology; D006949:Hyperlipidemias / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D013977:Tibia / Q000187:drug effects* / Q000503:physiopathology; D014057:Tomography, X-Ray Computed
chemical_list: D045930:Anabolic Agents; D017931:DNA Primers; D010281:Parathyroid Hormone; D011973:Receptors, LDL