Bone Loss and Its Prevention in HIV Patients

说明(由申请人提供)：艾滋病毒蛋白水解酶抑制剂的使用 (PIS)与其他抗逆转录病毒药物联合使用是戏剧性的核心 艾滋病毒感染的发病率和死亡率下降。我们的小组最近 发现接受PI治疗的患者骨密度(BMD)降低， 这导致我们研究了单独的PIS对成骨细胞(OB)和 破骨细胞的形成和功能。我们发现一种名为依地那韦的诱导剂 小鼠的骨丢失。该药通过抑制肥胖来发挥其骨质疏松作用。 前体分化，在这样做的过程中，抑制了特定的 成骨细胞转录因子Cbfal。与骨质疏松症 依地那韦的性质，利托那韦是一种节骨剂，在体内，发挥其 通过钝化OC的形成和功能，以非M-CSF的方式发挥作用。 由于破骨细胞的形成只需要M-CSF和RANKL，因此该药物 必须影响RANKL发起的信令。最后，我们提供了融合的数据 含有连接到RANKL胞外结构域的GST的蛋白质是一种有效的骨骼 合成代谢剂。因此，我们假设：1.印地那韦止骨 通过抑制Cbfal在OB前体中的表达而形成；2.利托那韦，通过 钝化RANKL诱导的信号转导，抑制OC分化和功能； 3.服用利托那韦或GST-RANKL将阻止和/或抢救 吲哚那韦引起的骨质疏松。因此，我们的具体目标是确定：1. 结论：1.依地那韦抑制去卵巢前体细胞Cbfal表达的机制； 利托那韦在OCS和OCS中钝化RANKL诱导信号的机制 它们的前体；3.如果服用利托那韦或GST-RANKL将阻止 和/或挽救因地那韦引起的骨质疏松症。

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.