Is PPARγ a Prospective Player in HIV‐1‐Associated Bone Disease?

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 gamma (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.

Lower bone density and microarchitecture alterations in HIV‐infected Brazilian men aged 50 years and older are associated with estradiol levels

“…PPARγ has been shown to be directly associated with bone turnover and bone loss, and with inhibition of aromatase activity. 33,34 Our findings strongly suggest that reduced E 2 is an independent factor for the overall bone alterations observed in MLWH. Because low BMI and body fat only influenced cortical bone parameters (area, density, and thickness) mostly at the distal tibia, a decreased weightbearing effect may also contribute to bone disease.…”

“…The fat distribution patterns of MLWH suggested lipodystrophy (higher trunk‐to‐total fat mass and lower leg fat mass than controls), which is related to PPARγ. PPARγ has been shown to be directly associated with bone turnover and bone loss, and with inhibition of aromatase activity 33,34 …”

HIV-1 and recombinant gp120 affect the survival and differentiation of human vessel wall-derived mesenchymal stem cells

“…In addition, Rev and p55 were able to activate PPARγ in MSCs from bone marrow [ 41 ]. These observations suggested that the modulation of PPARγ by HIV proteins during HIV infection may be considered a co-factor in the lipid and bone derangement observed during the HIV infection and in some antiretroviral treatments [ 79 ]. Our data also showed that viral infection and gp120 exposure induced an up-regulation of C/EBPβ and δ mRNA expressions demonstrating that adipogenesis positive modulation is determined until the first differentiation molecular steps.…”

HIV and Bone Loss

“…The balance between Runx2 and peroxisome proliferatoractivated receptor-γ (PPAR-γ) leads to mesenchymal differentiation into osteoblasts or adipocytes, depending on the relative activity of Runx2 and PPAR-γ, respectively [32].…”