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J. Biol. Chem., Vol. 282, Issue 29, 21237-21243, July 20, 2007

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Atherogenic Phospholipids Attenuate Osteogenic Signaling by BMP-2 and Parathyroid Hormone in Osteoblasts^*

Michael S. Huang, Sean Morony^¶, Jinxiu Lu^||, Zina Zhang, Olga Bezouglaia^**, Wendy Tseng, Sotirios Tetradis^**, Linda L. Demer^||, and Yin Tintut¹

From the Departments of Medicine, ^||Physiology, and Molecular Cellular Integrative Physiology, ^**Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California at Los Angeles, California 90095 and ^¶Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, California 91320

Cardiovascular disease, such as atherosclerosis, has been associated with reduced bone mineral density and fracture risk. A major etiologic factor in atherogenesis is believed to be oxidized phospholipids. We previously found that these phospholipids inhibit spontaneous osteogenic differentiation of marrow stromal cells, suggesting that they may account for the clinical link between atherosclerosis and osteoporosis. Currently, anabolic agents that promote bone formation are increasingly used as a new treatment for osteoporosis. It is not known, however, whether atherogenic phospholipids alter the effects of bone anabolic agents, such as bone morphogenetic protein (BMP)-2 and parathyroid hormone (PTH). Therefore we investigated the effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) on osteogenic signaling induced by BMP-2 and PTH in MC3T3-E1 cells. Results showed that ox-PAPC attenuated BMP-2 induction of osteogenic markers alkaline phosphatase and osteocalcin. Ox-PAPC also inhibited both spontaneous and BMP-induced expression of PTH receptor. Consistently, pretreatment of cells with ox-PAPC inhibited PTH-induced cAMP production and expression of immediate early genes Nurr1 and IL-6. Results from immunofluorescence and Western blot analyses showed that inhibitory effects of ox-PAPC on BMP-2 signaling were associated with inhibition of SMAD 1/5/8 but not p38-MAPK activation. These effects appear to be due to ox-PAPC activation of the ERK pathway, as the ERK inhibitor PD98059 reversed ox-PAPC inhibitory effects on BMP-2-induced alkaline phosphatase activity, osteocalcin expression, and SMAD activation. These results suggest that atherogenic lipids inhibit osteogenic signaling induced by BMP-2 and PTH, raising the possibility that hyperlipidemia and atherogenic phospholipids may interfere with anabolic therapy.

Received for publication, February 15, 2007 , and in revised form, May 22, 2007.

^* This work was supported by National Institutes of Health Grants DK076009-01 (to Y. T.) and HL081202 (to L. L. D.) and by Molecular Cellular and Integrative Physiology Training Grant NIGMS T32 GM065823 (to S. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: UCLA, Dept. of Medicine, CHS BH-307, 10833 Le Conte Ave., Los Angeles, CA 90095. Tel.: 310-206-9964; Fax: 310-825-4963; E-mail: ytintut{at}mednet.ucla.edu.

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