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 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.

Figure 1

Factors governing normal osteogenesis and adipogenesis from mesenchymal stem cells. Multipotent mesenchymal stem cells can differentiate into a number of cell types, including adipocytes and osteoblasts. (⊥ indicates inhibition; ↓ indicates stimulation). The transcriptional coactivator Taz negatively regulates adipogenesis and promotes osteogenesis through suppression of PPARγ and activation of RUNX-2, while overexpression of PPARγ can reduce bone formation. Also, a number of other factors such as secreted proteins from Wnt family promote the differentiation and maintenance of osteoblasts while reducing the differentiation of the adipocytes. In addition, factors secreted by mature adipocytes, such as leptin and estrogen, can increase bone mass in vivo.