NEW TARGETS TO PREVENT BONE AND JOINT DESTRUCTION

预防骨骼和关节破坏的新目标

• 批准号: 6310708
• 负责人: PAULA H STERN
• 金额: $ 17.42万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6310708
• 关键词: G protein; HMG coA reductases; analog; antibiotics; colony stimulating factor; cytokine; drug screening /evaluation; enzyme inhibitors; isoprenoid; laboratory mouse; lovastatin; mixed tissue /cell culture; osteoclast activating factor; osteoclasts; pathologic bone resorption

Osteoclastic bone resorption mediated by inflammatory cytokines is an important contributor to morbidity in patients with rheumatoid arthritis. Development of agents that could prevent or alleviate this bone loss would represent an important clinical advance. Screening of natural products has revealed several classes of agents that would be potentially effective as new anti-resorptive agents due to their ability to interfere with critical steps in osteoclast differentiation and action. The two compounds that would be investigated in the current proposal, compactin and reveromycin A, inhibit osteoclast activity. Compactin prevents osteoclast differentiation by inhibiting fusion of preosteoclasts mediated by Osteoclast Differentiating Factor (ODF) and Macrophage- Colony Stimulating Factor (M-CSF). It also disrupts the actin rings that are crucial to the resorptive activity of mature osteoclasts. Compactin is an HMG-CoA reductase inhibitor and its effects on osteoclasts appear to involve the decreased production of isoprenyl moieties through this pathway. Small G-proteins are critical targets for activation by isoprenylation, and this activation is critical for cytoskeletal function. The current proposal would determine the G-protein targets that are affected by the inflammatory cytokines and compactin in two osteoclast models, osteoclasts deriving from marrow/osteoblast co- cultures and the RAW 264.7 osteoclastogenic macrophage cell line and determine whether the inhibition of their isoprenylation is the mechanism of the inhibitory effect of compactin. Reveromycin A targets are less well defined, but may involve increased osteoclast apoptosis through activation of caspase 3. The studies would determine if this is a potential site of interaction between reveromycin and cytokines, and would identify other potential pathways and target molecules. Thus, the current proposal would help to elucidate the molecular mechanisms by which the actions of compactin and reveromycin A interfere with osteoclastic activity. Elucidation of the mechanism of these compounds could lead to a greater understanding of pathological bone loss and could result in the development of effective new therapeutic agents.

炎性细胞因子介导的破骨骨吸收是类风湿关节炎患者发病的重要原因。可以预防或减轻这种骨质流失的药物的发展将代表重要的临床进步。天然产物的筛选揭示了几类药物，它们可能会作为新的抗敏化剂有效，因为它们能够干扰破骨细胞分化和作用的关键步骤。在当前的建议和霉素A中将研究的两种化合物抑制破骨细胞活性。通过抑制由破骨细胞分化因子（ODF）和巨噬细胞刺激因子（M-CSF）介导的骨细胞融合来阻止破骨细胞分化。它还破坏了对成熟破骨细胞的吸收活性至关重要的肌动蛋白环。压缩蛋白是一种HMG-COA还原酶抑制剂，其对破骨细胞的影响似乎涉及通过该途径减少异丙素基部分的产生。小的G蛋白是通过异丙肾上腺素激活的关键靶标，并且该激活对于细胞骨架功能至关重要。当前的建议将确定在两种破骨细胞模型中受炎症细胞因子和紧凑型影响的G蛋白靶标，这些模型是从骨髓/成骨细胞培养物中得出的破骨细胞，以及RAW 264.7骨质质型巨噬细胞系列，并确定其对抑制作用的抑制作用。 炎霉素A靶标的定义不太明确，但可能涉及通过激活caspase 3来增加破骨细胞凋亡。研究将确定这是否是磷酸霉素和细胞因子之间相互作用的潜在相互作用的位置，并确定其他潜在的途径和靶分子。因此，当前的建议将有助于阐明压缩蛋白和炎霉素的作用一种干扰整骨活性的分子机制。阐明这些化合物的机制可能会导致对病理骨质流失有更多的了解，并可能导致有效的新治疗剂的发展。