Select HIV protease inhibitors alter bone and fat metabolism ex vivo
Select HIV protease inhibitors alter bone and fat metabolism ex vivo
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DOI：
10.1074/jbc.c200069200
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发表时间：
2002-05-31
影响因子：
4.8
通讯作者：
Lenhard, JM
中科院分区：
文献类型：
--
作者：
Jain, RG;Lenhard, JM
人类免疫缺陷病毒(HIV)的治疗与脂肪代谢和骨密度的变化有关。本研究利用体外培养的破骨细胞、成骨细胞和脂肪细胞，研究了HIV蛋白水解酶抑制剂(PI)对骨吸收、骨形成和脂肪细胞分化的影响。用大鼠新生颅盖骨测定，在奈非那韦(NFV；47.2%，p=0.001)、吲哚那韦(34.6%，p=0.001)、沙奎那韦(24.3%，p=0.001)或利托那韦(18%，p=0.001)存在时，破骨细胞活性增加。相比之下，洛匹那韦(LPV)和氨丙那韦并没有增加破骨细胞的活性。在人骨髓间充质干细胞(HMSCs)中，Pis、LPV和NFV显著降低成骨细胞碱性磷酸酶活性和基因表达(p<；0.05)。LPV和NFV可减少钙沉积和骨整合蛋白的表达(p<；0.05)，而所研究的其他PI则没有。沙奎那韦和NFV对人骨髓间充质干细胞的成脂有强烈的抑制作用(P<0.001)，利托那韦和左旋咪唑对其有中等程度的抑制作用(40%，P<0.01)。脂肪细胞分化的标志物二酰甘油转移酶在NFV处理的hMSCs中的表达减少。氨丙那韦和吲哚那韦不影响脂肪生成或脂肪分解。这些结果表明，骨髓hMSCs的骨和脂肪的形成可能被部分而不是全部的PI协同下调。
Human immunodeficiency virus (HIV) therapies have been associated with alterations in fat metabolism and bone mineral density. This study examined the effects of HIV protease inhibitors (PIs) on bone resorption, bone formation, and adipocyte differentiation using ex vivo cultured osteoclasts, osteoblasts, and adipocytes, respectively. Osteoclast activity, measured using a rat neonatal calvaria assay, increased in the presence of nelfinavir (NFV; 47.2%, p = 0.001), indinavir (34.6%, p = 0.001), saquinavir (24.3%, p = 0.001), or ritonavir (18%, p < 0.01). In contrast, lopinavir (LPV) and amprenavir did not increase osteoclast activity. In human mesenchymal stem cells (hMSCs), the PIs LPV and NFV decreased osteoblast alkaline phosphatase enzyme activity and gene expression significantly (p < 0.05). LPV and NFV diminished calcium deposition and osteoprotegrin expression (p < 0.05), whereas the other PIs investigated did not. Adipogenesis of hMSCs was strongly inhibited by saquinavir and NFV (>50%,p < 0.001) and moderately inhibited by ritonavir and LPV (40%,p < 0.01). Expression of diacylglycerol transferase, a marker of adipocyte differentiation, decreased in hMSCs treated with NFV. Amprenavir and indinavir did not affect adipogenesis or lipolysis. These results suggest that bone and fat formation in hMSCs of bone marrow may be coordinately down-regulated by some but not all PIs.