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首页> 美国卫生研究院文献>Journal of the Boston Society of Medical Sciences >WNT/β-Catenin Signaling Is Involved in Regulation of Osteoclast Differentiation by Human Immunodeficiency Virus Protease Inhibitor Ritonavir
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WNT/β-Catenin Signaling Is Involved in Regulation of Osteoclast Differentiation by Human Immunodeficiency Virus Protease Inhibitor Ritonavir

机译：WNT /β-Catenin信号传导参与人类免疫缺陷病毒蛋白酶抑制剂利托那韦的破骨细胞分化调控。

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Untreated human immunodeficiency virus (HIV) infection is accompanied by reduced bone mineral density, which appears to be exacerbated by certain HIV protease inhibitors (PIs). The mechanisms leading to this apparent paradox, however, remain unclear. We have previously shown that, the HIV envelope glycoprotein gp120 used at levels similar those in plasmas of untreated HIV+ patients, induced expression of the osteoclast (OC) differentiation factor RANKL in CD4+ T cells. In addition, the HIV PI ritonavir abrogated the interferon-γ-mediated degradation of the RANKL nuclear adapter protein TRAF6, a physiological block to RANKL activity. Here, using oligonucleotide microarrays and quantitative polymerase chain reaction, we explored potential upstream mechanisms for these effects. Ritonavir, but not the HIV PIs indinavir or nelfinavir, up-regulated the production of transcripts for OC growth factors and the non-canonical Wnt Proteins 5B and 7B as well as activated promoters of nuclear factor-κB signaling, but suppressed genes involved in canonical Wnt signaling. Similarly, ritonavir blocked the cytoplasmic to nuclear translocation of β-catenin, the molecular node of the Wnt signaling pathway, in association with enhanced β-catenin ubiquitination. Exposure of OC precursors to LiCl, an inhibitor of the canonical Wnt antagonist GSK-3β, suppressed OC differentiation, as did adenovirus-mediated overexpression of β-catenin. These data identify, for the first time, a biologically relevant role for Wnt signaling via β-catenin in isolated OC precursors and the modulation of Wnt signaling by ritonavir. The reversal of these ritonavir-mediated changes by interferon-γ provides a model for possible intervention in this metabolic complication of HIV therapy.
机译：未经治疗的人类免疫缺陷病毒（HIV）感染会伴随骨矿物质密度降低，某些HIV蛋白酶抑制剂（PIs）似乎加剧了这种情况。然而，导致这种明显悖论的机制仍不清楚。先前我们已经表明，以未经治疗的HIV + 患者血浆中相似的水平使用HIV包膜糖蛋白gp120，可以诱导破骨细胞（OC）分化因子RANKL在CD4 + T细胞中表达。此外，HIV PI利托那韦消除了干扰素-γ介导的RANKL核衔接蛋白TRAF6的降解，这是RANKL活性的生理阻断。在这里，我们使用寡核苷酸微阵列和定量聚合酶链反应，探索了这些效应的潜在上游机制。利托那韦，而不是HIV PIs茚地那韦或奈非那韦，上调了OC生长因子和非经典Wnt蛋白5B和7B的转录产物以及核因子-κB信号的激活启动子，但抑制了与经典Wnt信令。类似地，利托那韦与增强的β-catenin泛素化结合，阻断了Wnt信号通路分子节点β-catenin的胞质至核易位。 OC前体暴露于经典Wnt拮抗剂GSK-3β的抑制剂LiCl中，抑制了OC的分化，腺病毒介导的β-catenin的过表达也是如此。这些数据首次确定了分离的OC前体中经由β-catenin的Wnt信号转导的生物学相关作用以及利托那韦对Wnt信号转导的调节。干扰素-γ逆转了利托那韦介导的这些变化，为可能干预HIV治疗的代谢并发症提供了模型。

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