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J. Biol. Chem., Vol. 278, Issue 48, 48251-48258, November 28, 2003

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HIV Envelope gp120-mediated Regulation of Osteoclastogenesis via Receptor Activator of Nuclear Factor B Ligand (RANKL) Secretion and Its Modulation by Certain HIV Protease Inhibitors through Interferon-/RANKL Cross-talk^*

J. Mohamad Fakruddin and Jeffrey Laurence

From the Laboratory for AIDS Virus Research, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021

Accelerated bone resorption leading to osteopenia and osteoporosis has been noted in human immunodeficiency virus (HIV) seropositive, treatment-naive patients, but it may be greatly increased in incidence in those receiving highly active anti-retroviral therapies that incorporate certain protease inhibitors (PI). The pathophysiology of these processes is unclear. We have documented the induction of the primary cytokine responsible for osteoclast differentiation and bone resorption, the receptor activator of nuclear factor B ligand (RANKL), in T cells exposed to soluble HIV-1 envelope glycoprotein gp120. Using a murine osteoclast precursor cell line as well as primary human osteoclast precursors, we demonstrate that pharmacologic levels of two PIs that are linked clinically to osteopenia, ritonavir and saquinavir, abrogate a physiological block to RANKL activity, interferon--mediated degradation of the RANKL signaling adapter protein, TRAF6 (tumor necrosis factor receptor-associated protein 6) in proteasomes. In contrast, indinavir and nelfinavir, PIs that may promote or stabilize bone formation in vivo, had no impact on this system. These findings offer a molecular basis for the acceleration of bone resorption by certain PIs and provide the first example of clinically useful drugs that can interfere with the cross-talk between RANKL and interferon- via the proteasome. They also suggest a novel therapeutic approach to HIV osteopenia through modulation of these two molecules.

Received for publication, May 5, 2003 , and in revised form, August 18, 2003.

^* This work was supported by National Institutes of Health Grants HL55646 and HL61849 and the Angelo Donghia and Hagedorn Funds (to J. L.) and by Scholar Award RF02652-27 from the American Foundation for AIDS Research (to J. M. F.). 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.

To whom correspondence should be addressed: Laboratory for AIDS Virus Research, Weill Medical College of Cornell University, 411 East 69th St., New York, NY 10021. Tel.: 212-746-2988; Fax: 212-746-8601; E-mail: jlaurenc{at}med.cornell.edu.

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