Parmodulins as an Anti-Resorptive and Anti-Inflammatory Therapy for Metabolic Bone Disease

总结： 目前代谢性骨病的治疗是有效的。然而，它们的使用与罕见的 但有显著的副作用，这限制了患者对它们的接受。使用最广泛的药物， 二膦酸盐和狄诺塞单抗抑制吸收和形成，这种双重作用可能导致 发生严重并发症（颌骨骨坏死和转子下骨折）。因此，我们认为， 迫切需要对这些病症有效的、具有降低的 并发症，更容易被患者接受。抑制再吸收的药剂的鉴定和 没有效果或刺激形成可能是寻找副作用较少的疗法的关键。 众所周知，炎症是代谢性骨病（如类风湿性关节炎）的重要组成部分。 关节炎、炎性肠病和牛皮癣以及骨质疏松症和佩吉特病。我们有 发现破骨细胞前体细胞在其生长过程中瞬时表达蛋白酶激活受体1（PAR 1）， 分化为成熟的破骨细胞。这是重要的，因为PAR 1调节多种反应， 细胞，包括炎症和凋亡。无论是在体外还是在体内，我们都发现PAR 1抑制炎症反应， 破骨细胞生成反应，特别是自PAR 1以来由肿瘤坏死因子α（TNFα）刺激的破骨细胞生成反应 缺陷细胞或小鼠对TNFα的反应显著增强。 PAR 1对炎症和凋亡的许多抑制作用是由激活的酶介导的， 蛋白C（APC）。最近，一组小分子，parmodulins，被鉴定为选择性的， PAR 1的激动剂/拮抗剂。这些药物模拟APC的凋亡和抗凋亡作用， 影响其抗凝血作用。在初步数据中，我们表明parmodulin，ML-161，特别是 抑制体外破骨细胞生成，而不影响成骨细胞胶原合成或碱性磷酸酶 活动在本申请中，我们将测试parmodulins是一种潜在的新疗法的假设， 代谢性骨疾病，这可能有较少的严重副作用。 在具体目标1中，我们将详细分析ML-161和NRD-21对体外 破骨细胞和成骨细胞的形成和功能。 在具体的目标2中，我们将检查ML-161和NRD-21抑制炎性细胞因子的体内能力。 骨对TNFα的反应。 如果成功的话，这些研究将为更详细地研究 parmodulins对由于性类固醇戒断、衰老和炎症引起的骨疾病小鼠模型的作用 条件

Summary: Current therapies for metabolic bone diseases are effective. However, their use is associated with rare but significant side effects, which limit their acceptance by patients. The most widely used drugs, bisphosphonates and denosumab, inhibit both resorption and formation and this dual action may lead to the development of severe complications (osteonecrosis of the jaw and sub-trochanteric fractures). Therefore, there is a pressing need for new therapies for these conditions that are effective, have a decreased risk of complications and will be more accepted by patients. The identification of agents that inhibit resorption and either have no effect or stimulate formation is likely critical for finding therapies with fewer side effects. Inflammation is known to be a significant component of metabolic bone diseases like rheumatoid arthritis, inflammatory bowel disease and psoriasis and also osteoporosis and Paget's disease. We have found that osteoclast precursor cells transiently express protease activated receptor 1 (PAR1) during their differentiation into mature osteoclasts. This is significant because PAR1 modulates a variety of responses in cells, including inflammation and apoptosis. Both in vitro and in vivo we found that PAR1 inhibited inflammatory osteoclastogenic responses, particularly those stimulated by tumor necrosis factor α (TNFα) since in PAR1 deficient cells or mice responses to TNFα were markedly enhanced. Many inhibitory effects of PAR1 on inflammation and apoptosis are mediated by the enzyme, activated protein C (APC). Recently, a group of small molecules, the parmodulins, were identified as selective agonist/antagonists of PAR1. These agents mimic APC's antiinflammatory and antiapoptotic actions, without affecting its anticoagulative action. In preliminary data we show that the parmodulin, ML-161, specifically inhibited in vitro osteoclastogenesis without affecting osteoblast collagen synthesis or alkaline phosphatase activity. In this application we will test the hypothesis that parmodulins are a potential new therapy for metabolic bone diseases, which may have fewer serious side effects. In specific aim 1 we will provide a detailed analysis of the effects of ML-161 and NRD-21 on in vitro osteoclast and osteoblast formation and function. In specific aim 2 we will examine the in vivo ability of ML-161 and NRD-21 to inhibit the inflammatory response of bone to TNFα. If successful, these studies will provide the foundation for more detailed studies of the effects of parmodulins on murine models of bone disease due to sex steroid withdrawal, aging and inflammatory conditions.