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首页> 外文期刊>Aging cell. >The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation
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The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation

机译：HIV蛋白Tat和Nef促进人骨髓间充质干细胞衰老并改变成骨细胞分化

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SummaryTo 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.
机译：总结为了维持骨量转换和骨矿物质密度（BMD），不断募集骨髓（BM）间充质干细胞（MSC），然后分化为成骨细胞。与未感染HIV的个体相比，感染HIV的患者的BMD更低，骨质疏松症/骨质疏松症的患病率更高。在未接受抗逆转录病毒治疗（ART）的患者中，编码的HIV蛋白代表致病候选物。它们由BM中的感染细胞释放，并可能影响邻近细胞。在这项研究中，我们测试了HIV蛋白Tat和/或Nef是否可以诱导人BM-MSC衰老并降低其分化为成骨细胞的能力。与未经处理的细胞相比，经Tat和/或Nef长期治疗长达30天的MSC降低了它们的增殖活性并经历了早期衰老，这与氧化应激和线粒体功能障碍增加有关。抗氧化剂分子N-乙酰半胱氨酸对Tat或Nef诱导的衰老没有影响或影响很小。 Tat而非Nef诱导NF-κB活性和细胞因子/趋化因子分泌的早期增加。 Tat诱导的作用被NF-κB抑制剂小白菊内酯所阻止，这表明Tat通过NF-κB活化导致氧化应激而触发衰老。否则，Nef处理的细胞（而非Tat处理的细胞）显示出自噬的早期抑制。自噬诱导剂雷帕霉素逆转了Nef诱导的衰老和氧化应激。此外，Tat + Nef具有累积效应。最后，Tat和/或Nef降低了成骨细胞分化的MSC潜力。总之，我们的体外数据表明，Tat和Nef可以通过增强炎症或减少自噬来诱导MSC衰老，从而减少可用前体的数量。这些结果为HIV感染患者BMD降低的病理生理机制提供了新的见解。

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