Open AccessHIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin
Author(s) -
HernandezVallejo Sandra J.,
Beaupere Carine,
Larghero Jerome,
Capeau Jacqueline,
Lagathu Claire
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12119
Subject(s) - mesenchymal stem cell , pravastatin , osteoblast , senescence , biology , ritonavir , lopinavir , premature aging , bone marrow , stem cell , cancer research , endocrinology , medicine , microbiology and biotechnology , immunology , biochemistry , cholesterol , viral load , physiology , human immunodeficiency virus (hiv) , antiretroviral therapy , in vitro
Summary HIV‐infected patients receiving antiretroviral therapy present an increased prevalence of age‐related comorbidities, including osteoporosis. HIV protease inhibitors ( PI s) have been suspected to participate to bone loss, but the mechanisms involved are unknown. In endothelial cells, some PI s have been shown to induce the accumulation of farnesylated prelamin‐ A , a biomarker of cell aging leading to cell senescence. Herein, we hypothesized that these PI s could induce premature aging of osteoblast precursors, human bone marrow mesenchymal stem cells ( MSC s), and affect their capacity to differentiate into osteoblasts. Senescence was studied in proliferating human MSC s after a 30‐day exposure to atazanavir and lopinavir with or without ritonavir. When compared to untreated cells, PI ‐treated MSC s had a reduced proliferative capacity that worsened with increasing passages. PI treatment led to increased oxidative stress and expression of senescence markers, including prelamin‐ A . Pravastatin, which blocks prelamin‐ A farnesylation, prevented PI ‐induced senescence and oxidative stress, while treatment with antioxidants partly reversed these effects. Moreover, senescent MSC s presented a decreased osteoblastic potential, which was restored by pravastatin treatment. Because age‐related bone loss is associated with increased bone marrow fat, we also evaluated the capacity of PI ‐treated MSC s to differentiate into adipocyte. We observed an altered adipocyte differentiation in PI ‐treated MSC s that was reverted by pravastatin. We have shown that some PI s alter osteoblast formation by affecting their differentiation potential in association with altered senescence in MSC s, with a beneficial effect of statin. These data corroborate the clinical observations and allow new insight into pathophysiological mechanisms of PI ‐induced bone loss in HIV ‐infected patients.