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J. Biol. Chem., Vol. 282, Issue 12, 8959-8968, March 23, 2007

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Oxysterols Are Novel Activators of the Hedgehog Signaling Pathway in Pluripotent Mesenchymal Cells^*

Jennifer R. Dwyer, Navdar Sever¹, Marc Carlson^¶, Stanley F. Nelson^¶, Philip A. Beachy², and Farhad Parhami³

From the Departments of Medicine and ^¶Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, and the Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305

Pluripotent mesenchymal cells form a population of precursors to a variety of cell types, including osteoblasts and adipocytes. Aging tilts the balance in favor of adipocyte differentiation at the expense of osteoblast differentiation, resulting in reduced bone formation and osteopenic disorders, including osteoporosis, in humans and animals. Understanding the mechanisms involved in causing this apparent shift in differentiation and identifying factors that stimulate osteoblast formation while inhibiting adipogenesis are of great therapeutic interest. In this study we report that specific, naturally occurring oxysterols, previously shown to direct pluripotent mesenchymal cells toward an osteoblast lineage, exert their osteoinductive effects through activation of Hedgehog signaling pathway. This was demonstrated by 1) oxysterol-induced expression of the Hh target genes Gli-1 and Patched, 2) oxysterol-induced activation of a luciferase reporter driven by a multimerized Gli-responsive element, 3) inhibition of oxysterol effects by the hedgehog pathway inhibitor, cyclopamine, and 4) unresponsiveness of Smoothened^-/- mouse embryonic fibroblasts to oxysterols. Using Patched^-/- cells that possess high baseline Gli activity, we found that oxysterols did not dramatically shift the IC₅₀ concentration of cyclopamine needed to inhibit Gli activity in these cells. Furthermore, binding studies showed that oxysterols did not compete with fluorescently labeled cyclopamine, BODIPY-cyclopamine, for direct binding to Smoothened. These findings demonstrate that oxysterols stimulate hedgehog pathway activity by indirectly activating the seven-transmembrane pathway component Smoothened. Osteoinductive oxysterols are, therefore, novel activators of the hedgehog pathway in pluripotent mesenchymal cells, and they may be important modulators of this critical signaling pathway that regulates numerous developmental and post-developmental processes.

Received for publication, December 21, 2006

^* This work was supported in part by NIAMS, National Institutes of Health (NIH) Grant RO1AR050426 and NIH Grant HL30568. 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 A Philip O'Bryan Montgomery, Jr., M.D. fellow of the Damon Runyon Cancer Research Foundation.

² An investigator of the Howard Hughes Medical Institute.

³ To whom correspondence should be addressed: David Geffen School of Medicine at UCLA, Center for the Health Sciences, BH-307, 10833 Le Conte Ave., Los Angeles, CA 90095. Tel.: 310-825-5729; Fax: 310-206-9133; E-mail: fparhami{at}mednet.ucla.edu.

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