title: The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation.
abstract: To maintain bone mass turnover and bone mineral density (BMD), bone marrow (BM) mesenchymal stem cells (MSCs) are constantly recruited and subsequently differentiated into osteoblasts. HIV-infected patients present lower BMD than non-HIV infected individuals and a higher prevalence of osteopenia/osteoporosis. In antiretroviral treatment (ART)-naive patients, encoded HIV proteins represent pathogenic candidates. They are released by infected cells within BM and can impact on neighbouring cells. In this study, we tested whether HIV proteins Tat and/or Nef could induce senescence of human BM-MSCs and reduce their capacity to differentiate into osteoblasts. When compared to nontreated cells, MSCs chronically treated with Tat and/or Nef up to 30 days reduced their proliferative activity and underwent early senescence, associated with increased oxidative stress and mitochondrial dysfunction. The antioxidant molecule N-acetyl- cysteine had no or minimal effects on Tat- or Nef-induced senescence. Tat but not Nef induced an early increase in NF-κB activity and cytokine/chemokine secretion. Tat-induced effects were prevented by the NF-κB inhibitor parthenolide, indicating that Tat triggered senescence via NF-κB activation leading to oxidative stress. Otherwise, Nef- but not Tat-treated cells displayed early inhibition of autophagy. Rapamycin, an autophagy inducer, reversed Nef-induced senescence and oxidative stress. Moreover, Tat+Nef had cumulative effects. Finally, Tat and/or Nef decreased the MSC potential of osteoblastic differentiation. In conclusion, our in vitro data show that Tat and Nef could reduce the number of available precursors by inducing MSC senescence, through either enhanced inflammation or reduced autophagy. These results offer new insights into the pathophysiological mechanisms of decreased BMD in HIV-infected patients.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Beaupere
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Inserm, UMR1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010, Paris, France.|AP-HP, Unité de Thérapie Cellulaire et CIC de Biothérapies, Hôpital Saint Louis, Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, F-75475, Paris, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Larghero
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|Institute of Cardiometabolism and Nutrition, Paris, France.|APHP, Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fève
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|Institute of Cardiometabolism and Nutrition, Paris, France.|APHP, Hôpital Tenon, F-75020, Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.|Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Lagathu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D011994:Recombinant Proteins / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; D015675:Osteocalcin; C002669:parthenolide; D020123:Sirolimus; D000111:Acetylcysteine
keywords: HIV proteins; autophagy; inflammation; osteoblastic differentiation; oxidative stress; senescence
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