Role of Paraoxonase-1 in Bone Anabolic Effects of Parathyroid Hormone in Hyperlipidemic Mice

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2013 Jan 8

PMID 23291186

Citations 4

Authors

Jinxiu Lu

Henry Cheng

Elisa Atti

Diana M Shih

Linda L Demer

Yin Tintut

Affiliations

Soon will be listed here.

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.

Citing Articles

Single nucleotide polymorphism rs854560 in paraoxonase-1 regulates the cytodifferentiation of human periodontal ligament cells.

Masumoto R, Fujihara C, Matsumoto M, Kitagaki J, Murakami S Front Dent Med. 2025; 5:1449482.

PMID: 39917667 PMC: 11797752. DOI: 10.3389/fdmed.2024.1449482.

Prevention and treatment of peri-implant fibrosis by functionally inhibiting skeletal cells expressing the leptin receptor.

Suhardi V, Oktarina A, Hammad M, Niu Y, Li Q, Thomson A Nat Biomed Eng. 2024; 8(10):1285-1307.

PMID: 39085645 DOI: 10.1038/s41551-024-01238-y.

Differentially expressed serum proteins associated with calcium regulation and hypocalcemia in dairy cows.

Shu S, Bai Y, Wang G, Xiao X, Fan Z, Zhang J Asian-Australas J Anim Sci. 2016; 30(6):893-901.

PMID: 27809461 PMC: 5411855. DOI: 10.5713/ajas.16.0615.

Effects of bioactive lipids and lipoproteins on bone.

Tintut Y, Demer L Trends Endocrinol Metab. 2013; 25(2):53-9.

PMID: 24183940 PMC: 3946677. DOI: 10.1016/j.tem.2013.10.001.

Roles of parathyroid hormone (PTH) receptor and reactive oxygen species in hyperlipidemia-induced PTH resistance in preosteoblasts.

Li X, Garcia J, Lu J, Iriana S, Kalajzic I, Rowe D J Cell Biochem. 2013; 115(1):179-88.

PMID: 24038594 PMC: 3889484. DOI: 10.1002/jcb.24648.

References

Sorenson R, Teiber J, La Du B . The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics. 1996; 33(3):498-507. DOI: 10.1006/geno.1996.0225. View

Towler D . Oxidation, inflammation, and aortic valve calcification peroxide paves an osteogenic path. J Am Coll Cardiol. 2008; 52(10):851-4. PMC: 2559856. DOI: 10.1016/j.jacc.2008.05.044. View

Parhami F, Morrow A, Balucan J, Leitinger N, Watson A, Tintut Y . Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol. 1997; 17(4):680-7. DOI: 10.1161/01.atv.17.4.680. View

Bhattacharyya T, Nicholls S, Topol E, Zhang R, Yang X, Schmitt D . Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008; 299(11):1265-76. PMC: 3014051. DOI: 10.1001/jama.299.11.1265. View

Morony S, Tintut Y, Zhang Z, Cattley R, Van G, Dwyer D . Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(-/-) mice. Circulation. 2008; 117(3):411-20. PMC: 2680735. DOI: 10.1161/CIRCULATIONAHA.107.707380. View

Kulkarni N, Halladay D, Miles R, Gilbert L, Frolik C, Galvin R . Effects of parathyroid hormone on Wnt signaling pathway in bone. J Cell Biochem. 2005; 95(6):1178-90. DOI: 10.1002/jcb.20506. View

Jilka R, Almeida M, Ambrogini E, Han L, Roberson P, Weinstein R . Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration. Aging Cell. 2010; 9(5):851-67. PMC: 2958819. DOI: 10.1111/j.1474-9726.2010.00616.x. View

Hjortnaes J, Butcher J, Figueiredo J, Riccio M, Kohler R, Kozloff K . Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur Heart J. 2010; 31(16):1975-84. PMC: 2921509. DOI: 10.1093/eurheartj/ehq237. View

Huang M, Lu J, Ivanov Y, Sage A, Tseng W, Demer L . Hyperlipidemia impairs osteoanabolic effects of PTH. J Bone Miner Res. 2008; 23(10):1672-9. PMC: 2576281. DOI: 10.1359/jbmr.080513. View

10.

Tintut Y, Morony S, Demer L . Hyperlipidemia promotes osteoclastic potential of bone marrow cells ex vivo. Arterioscler Thromb Vasc Biol. 2003; 24(2):e6-10. DOI: 10.1161/01.ATV.0000112023.62695.7f. View

11.

Robling A, Kedlaya R, Ellis S, Childress P, Bidwell J, Bellido T . Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology. 2011; 152(8):2963-75. PMC: 3138236. DOI: 10.1210/en.2011-0049. View

12.

Huang M, Morony S, Lu J, Zhang Z, Bezouglaia O, Tseng W . Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and parathyroid hormone in osteoblasts. J Biol Chem. 2007; 282(29):21237-43. PMC: 3001330. DOI: 10.1074/jbc.M701341200. View

13.

Pirih F, Lu J, Ye F, Bezouglaia O, Atti E, Ascenzi M . Adverse effects of hyperlipidemia on bone regeneration and strength. J Bone Miner Res. 2011; 27(2):309-18. PMC: 3274629. DOI: 10.1002/jbmr.541. View

14.

Xiong J, Onal M, Jilka R, Weinstein R, Manolagas S, OBrien C . Matrix-embedded cells control osteoclast formation. Nat Med. 2011; 17(10):1235-41. PMC: 3192296. DOI: 10.1038/nm.2448. View

15.

Tintut Y, Parhami F, Tsingotjidou A, Tetradis S, Territo M, Demer L . 8-Isoprostaglandin E2 enhances receptor-activated NFkappa B ligand (RANKL)-dependent osteoclastic potential of marrow hematopoietic precursors via the cAMP pathway. J Biol Chem. 2002; 277(16):14221-6. DOI: 10.1074/jbc.M111551200. View

16.

Watson A, Berliner J, Hama S, La Du B, Faull K, Fogelman A . Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995; 96(6):2882-91. PMC: 185999. DOI: 10.1172/JCI118359. View

17.

Huang M, Sage A, Lu J, Demer L, Tintut Y . Phosphate and pyrophosphate mediate PKA-induced vascular cell calcification. Biochem Biophys Res Commun. 2008; 374(3):553-8. PMC: 2570192. DOI: 10.1016/j.bbrc.2008.07.062. View

18.

Brodeur M, Brissette L, Falstrault L, Ouellet P, Moreau R . Influence of oxidized low-density lipoproteins (LDL) on the viability of osteoblastic cells. Free Radic Biol Med. 2008; 44(4):506-17. DOI: 10.1016/j.freeradbiomed.2007.08.030. View

19.

Shih D, Gu L, Xia Y, Navab M, Li W, Hama S . Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature. 1998; 394(6690):284-7. DOI: 10.1038/28406. View

20.

Hirasawa H, Tanaka S, Sakai A, Tsutsui M, Shimokawa H, Miyata H . ApoE gene deficiency enhances the reduction of bone formation induced by a high-fat diet through the stimulation of p53-mediated apoptosis in osteoblastic cells. J Bone Miner Res. 2007; 22(7):1020-30. DOI: 10.1359/jbmr.070330. View