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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
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Modulation of osteoclastogenesis induced by nucleoside reverse transcriptase inhibitors

George Pan1, Michael Kilby, Jay M McDonald

  • 1Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

AIDS Research and Human Retroviruses
|December 7, 2006
PubMed

Osteopenia is a common and debilitating side-effect of HAART, yet little is known concerning the effects of HAART on bone metabolism. We reported previously that zidovudine (AZT) stimulates osteoclastogenesis in vitro and causes osteopenia in mice. Here, we confirmed that the AZT-induced osteoclastogenesis is dependent on RANKL in that osteoclastogenesis is blocked by osteoprotegestin. Alendronate, which is used for the treatment of osteopenia and osteoporosis, failed to inhibit AZT-induced osteoclastogenesis in vitro. Osteoclastogenesis in vitro was not affected by tumor necrosis factor-alpha. Two other NRTI drugs, ddl and 3TC, also induced osteoclastogenesis in vitro and induced osteopenia in mice. The osteopenia was associated with an elevation of parameters of osteoclasts, but not with osteoblasts. Combinations of the NRTIs did not result in additive or synergistic effects in vitro or in vivo. Finally, AZT induced osteoclastogenesis of human osteoclast precursors in a RANKL-dependent manner. This in vitro osteoclastogenesis assay using human peripheral blood mononuclear cells could be useful in evaluating bone turnover and the risk of developing osteopenia in AIDS patients on HAART.

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