The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation.
The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation.
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DOI：
10.1111/acel.12308
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发表时间：
2015-08
期刊：
影响因子：
7.8
通讯作者：
Lagathu C
中科院分区：
文献类型：
--
作者：
Beaupere C;Garcia M;Larghero J;Fève B;Capeau J;Lagathu C
为了维持骨量转换和骨矿物质密度（BMD），骨髓（BM）间充质干细胞（MSC）不断招募，随后分化为成骨细胞。HIV感染者的BMD低于非HIV感染者，骨量减少/骨质疏松症的患病率更高。在抗逆转录病毒治疗（ART）初治患者中，编码的HIV蛋白代表致病候选者。它们由BM内受感染的细胞释放，并可影响邻近细胞。在这项研究中，我们测试了HIV蛋白达特和/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。当与未处理的细胞相比时，用达特和/或Nef长期处理长达30天的MSC降低其增殖活性并经历与增加的氧化应激和线粒体功能障碍相关的早期衰老。抗氧化分子N-乙酰半胱氨酸对达特或Nef诱导的衰老没有影响或影响极小。达特而不是Nef诱导NF-κB活性和细胞因子/趋化因子分泌的早期增加。Tat诱导的效应被NF-κB抑制剂parthenoprotein阻止，表明达特通过NF-κB激活导致氧化应激而触发衰老。另外，Nef处理的细胞而不是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可逆转Nef诱导的衰老和氧化应激。此外，达特+Nef具有累积效应。最后，达特和/或Nef降低了MSC的成骨分化潜能。总之，我们的体外数据表明，达特和Nef可以通过增强炎症或减少自噬诱导MSC衰老来减少可用前体的数量。这些结果提供了新的见解艾滋病毒感染患者骨密度降低的病理生理机制。
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.