Bone Loss and Its Prevention in HIV Patients

HIV患者的骨质流失及其预防

• 批准号: 6879116
• 负责人: F. Patrick ROSS
• 金额: $ 33.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-11 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879116
• 关键词: HIV infections; antiAIDS agent; biological signal transduction; bone density; bone metabolism disorder; cell differentiation; disease /disorder prevention /control; drug adverse effect; high performance liquid chromatography; immunoprecipitation; indinavir; laboratory mouse; ligands; osteoblasts; osteoclasts; osteogenesis; osteoporosis; osteoprotegerin; pathologic bone resorption; pharmacokinetics; polymerase chain reaction; protease inhibitor; ritonavir; skeletal pharmacology; tissue /cell culture; transcription factor

DESCRIPTION (Provided by the applicant): The use of HIV protease inhibitors (PIS), combined with other anti-retroviral agents, is central to dramatic decline in the morbidity and mortality of HIV infection. Our group recently discovered that PI-treated patients have decreased bone mineral density (BMD), which led us to examine the effects of individual PIS on osteoblast (OB) and osteoclast (OC) formation and function. We find that one PI, Indinavir, induces bone loss in mice. The drug exerts its osteoporotic effect by arresting OB precursor differentiation, and in so doing, dampens expression of the specific osteoblast transcription factor, Cbfal. In contrast to the osteoporotic properties of Indinavir, Ritonavir is bone sparing, in vivo, exerting its effect, in an M-CSF independent manner, by blunting OC formation and function. Since osteoclastogenesis requires only M-CSF and RANK ligand (RANKL) the drug must impact RANKL-initiated signaling. Finally, we provide data that a fusion protein comprising GST linked to the ectodomain of RANKL is a potent bone anabolic agent. We therefore hypothesize that: 1. lndinavir arrests bone formation by inhibiting Cbfal expression in OB precursors; 2. Ritonavir, by blunting RANKL-induced signaling, inhibits OC differentiation and function; and 3. Administration of Ritonavir, or GST-RANKL, will prevent andlor rescue Indinavir-induced osteoporosis. Thus, our specific aims are to determine: 1. the mechanism by which lndinavir inhibits Cbfal expression in OB precursors; 2. The mechanism by which Ritonavir, blunts RANKL-induced signaling, in OCs and their precursors; 3. If administration of Ritonavir, or GST-RANKL, will prevent and/or rescue Indinavir-induced osteoporosis.

描述（由申请方提供）：HIV蛋白酶抑制剂的用途 (PIS)结合其他抗逆转录病毒药物， 艾滋病毒感染的发病率和死亡率下降。我们组最近 发现PI治疗的患者骨矿物质密度（BMD）降低， 这使我们研究了单个PIS对成骨细胞（OB）的影响， 破骨细胞（OC）的形成和功能。我们发现一种PI，茚地那韦， 小鼠的骨质流失。这种药物通过阻止OB的生长而发挥其抗肿瘤作用 前体分化，并在这样做，抑制表达的具体 成骨细胞转录因子Cbfal。与骨质疏松症相反 利托那韦是茚地那韦的特性，在体内， 以M-CSF非依赖性方式，通过钝化OC形成和功能来影响。 由于破骨细胞生成仅需要M-CSF和RANK配体（RANKL）， 必须影响RANKL发起的信令。最后，我们提供数据， 包含与RANKL的胞外域连接的GST的蛋白质是有效的骨诱导剂。 合成代谢剂。因此，我们假设：1。茚地那韦阻滞骨 通过抑制OB前体中的Cbfal表达形成; 2.利托那韦，通过 钝化RANKL诱导的信号传导，抑制OC分化和功能;和 3.利托那韦或GST-RANKL的给药将预防或挽救 茚地那韦引起的骨质疏松症。因此，我们的具体目标是确定：1。 茚地那韦抑制OB前体中Cbfal表达的机制; 2. 利托那韦减弱RANKL诱导的信号传导的机制， 其前身; 3。如果利托那韦或GST-RANKL给药可预防 和/或挽救茚地那韦诱导的骨质疏松症。