Article

The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling

Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 08/2004; 114(2):206-13. DOI: 10.1172/JCI15797
Source: PubMed

ABSTRACT Highly active antiretroviral therapy (HAART), which includes HIV protease inhibitors (PIs), has been associated with bone demineralization. To determine if this complication reflects accelerated resorptive activity, we studied the impact of two common HIV PIs, ritonavir and indinavir, on osteoclast formation and function. Surprisingly, we find that ritonavir, but not indinavir, inhibits osteoclast differentiation in a reversible manner and also abrogates bone resorption by disrupting the osteoclast cytoskeleton, without affecting cell number. Ritonavir given in vivo completely blunts parathyroid hormone-induced osteoclastogenesis in mice, which confirms that the drug is bone sparing. In keeping with its antiresorptive properties, ritonavir impairs receptor activator of nuclear factor kappaB ligand-induced (RANKL-induced) activation of NF-kappaB and Akt signaling pathways, both critical to osteoclast formation and function. In particular, ritonavir is found to inhibit RANKL-induced Akt signaling by disrupting the recruitment of TNF receptor-associated factor 6/c-Src complex to lipid rafts. Thus, ritonavir may represent a bone-sparing PI capable of preventing development of osteopenia in patients currently on HAART.

Full-text

Available from: Steven Teitelbaum, Sep 22, 2014
0 Followers
 · 
64 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a high prevalence of osteoarticular complications in human immunodeficiency virus (HIV)-infected patients. The widespread use of highly active antiretroviral therapy (HAART) has worked in a large number of older subjects living with HIV, improving the quality of life of HIV-positive individuals. However, at the same time, it has increased the prevalence of metabolic changes due to the prolonged period of viral infection and the treatment itself. Osteoarticular changes, including osteopenia/osteoporosis and osteonecrosis, have become an increasingly important problem in the era of HAART. In the following article we would like to evaluate osteoporosis in more detail. Osteoporosis is needed to define the optimal detection and treatment strategies as well as specific diagnosis of uncertain causes of this disease in HIV-infected patients.
    06/2011; 10(2):47-51. DOI:10.1016/j.hivar.2011.02.002
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Currently infection with the human immunodeficiency virus-1 (HIV-1) is in most instances a chronic disease that can be controlled by effective antiretroviral therapy (ART). However, chronic use of ART has been associated with a number of toxicities; including significant reductions in bone mineral density (BMD) and disorders of the fat metabolism. The peroxisome proliferator-activated receptor γ (PPARγ) transcription factor is vital for the development and maintenance of mature and developing adipocytes. Alterations in PPARγ expression have been implicated as a factor in the mechanism of HIV-1-associated lipodystrophy. Both reduced BMD and lipodystrophy have been well described as complications of HIV-1 infection and treatment, and a question remains as to their interdependence. Interestingly, both adipocytes and osteoblasts are derived from a common precursor cell type; the mesenchymal stem cell. The possibility that dysregulation of PPARγ (and the subsequent effect on both osteoblastogenesis and adipogenesis) is a contributory factor in the lipid- and bone-abnormalities observed in HIV-1 infection and treatment has also been investigated. This review deals with the hypothesis that dysregulation of PPARγ may underpin the bone abnormalities associated with HIV-1 infection, and treats the current knowledge and prospective developments, in our understanding of PPARγ involvement in HIV-1-associated bone disease.
    PPAR Research 02/2009; 2009:421376. DOI:10.1155/2009/421376 · 1.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A high incidence of decreased bone mineral density (BMD) has been associated with HIV infection. Normal skeletal homeostasis is controlled, at least in part, by the maturation and activity of mature osteoblasts. Previous studies by our group have demonstrated the ability of HIV proteins to perturb osteoblast function, and the degree of osteogenesis in differentiating mesenchymal stem cells (MSCs). This study attempts to further dissect the dynamics of this effect. MSCs were cultured under both osteogenic (cultured in commercially available differentiation media) and quiescent (cultured in basal medium) conditions. Both cell populations were exposed to HIV p55-gag and HIV rev (100 ng/ml). Time points were taken at 3, 6, 9, and 15 days for osteogenic conditions, while quiescent cells were treated for 1 week. Cell function (alkaline phosphatase [ALP] activity, calcium deposition, and lipid levels) and the activity of the key MSC transcription factors, RUNX-2 and PPARgamma were determined post-exposure. Also, in cells cultured in differentiating conditions, cellular levels of connective tissue growth factor (CTGF) were analysed using whole cell ELISA, while BMP-2 secretion was also examined. In differentiating MSCs, exposure to HIV proteins caused significant changes in both the timing and magnitude of key osteogenic events and signals. Treatment with REV increased the overall rate of mineralization, and induced earlier increases in CTGF levels, RUNX-2 activity and BMP-2 secretion, than those observed in the normal course of differntiation. In contrast, p55-gag reduced the overall level of osteogenesis, and reduced BMP-2 secretion, RUNX-2 activity, CTGF levels and ALP activity at many of the timepoints examined. Finally, in cells cultured in basal conditions, treatment with HIV proteins did not in and of itself induce a significant degree of differentiation over the time period examined. These data demonstrate that the effect of HIV proteins on bone is dependent on the differentiation status of the cells that they are in contact with. The effect on bone cell signalling provides insights into the mechanism of HIV induced decreases in bone mineral density.
    BMC Musculoskeletal Disorders 02/2008; 9:33. DOI:10.1186/1471-2474-9-33 · 1.90 Impact Factor