HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk.
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 kappa 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-gamma-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-gamma via the proteasome. They also suggest a novel therapeutic approach to HIV osteopenia through modulation of these two molecules.
Fakruddin
J Mohamad
JM
Laboratory for AIDS Virus Research, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Laurence
Jeffrey
J
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000378:metabolism; D001862:Bone Resorption; D017252:CD3 Complex / Q000096:biosynthesis; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D019469:Indinavir / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D019888:Nelfinavir / Q000494:pharmacology; D010010:Osteoclasts / Q000378:metabolism*; D011233:Precipitin Tests; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D019438:Ritonavir / Q000494:pharmacology
D017252:CD3 Complex; D002352:Carrier Proteins; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D017320:HIV Protease Inhibitors; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D019469:Indinavir; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D019888:Nelfinavir; D019438:Ritonavir