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

Parmodulins 作为代谢性骨疾病的抗吸收和抗炎疗法

• 批准号: 10055011
• 负责人: Joseph A Lorenzo
• 金额: $ 21.65万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055011
• 关键词: Actins; Affect; Aging; Agonist; Alkaline Phosphatase; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Bone Diseases; Bone Resorption; Bone necrosis; Calvaria; Cell Count; Cells; Characteristics; Collagen; Data; Development; Dose; Drug usage; Enzymes; Foundations; Gene Expression; Genes; Goals; Gonadal Steroid Hormones; Homeostasis; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injections; Jaw; Lead; Ligands; MAP Kinase Gene; Macrophage Colony-Stimulating Factor Receptor; Mature Bone; Measures; Mediating; Metabolic Bone Diseases; Minerals; Modeling; Monitor; Mus; Nodule; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Outcome; PAR-1 Receptor; Paget' s Disease; Pathway interactions; Patients; Protease Inhibitor; Psoriasis; Research; Rheumatoid Arthritis; Risk; Signal Pathway; Signal Transduction; Surveys; TNF gene; Testing; Trochanteric Fractures; Withdrawal; activated Protein C; bisphosphonate; bone; bone cell; cytokine; experimental study; factor A; high risk; in vivo; indexing; inflammatory bone loss; mouse model; notch protein; novel; novel therapeutics; osteoblast differentiation; osteoclastogenesis; overexpression; precursor cell; receptor; response; side effect; small molecule

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.

概括： 当前的代谢骨疾病疗法有效。但是，它们的使用与稀有 但是重大副作用，这限制了患者接受。使用最广泛的药物， 双膦酸盐和denosumab抑制了分辨率和形成，这种双重作用可能导致 发生严重并发症的发展（颌骨和亚细胞骨折的骨坏死）。所以， 对于这些有效的疾病的新疗法迫切需要，有降低的风险 并发症，将被患者接受。识别抑制分辨率和 没有作用或刺激形成对于寻找副作用较少的疗法可能至关重要。 已知炎症是类风湿的代谢骨疾病的重要组成部分 关节炎，炎症性肠病和牛皮癣以及骨质疏松症和paget病。我们有 发现破骨细胞前体细胞在其期间瞬时表达蛋白酶活化受体1（PAR1） 分化为成熟的破骨细胞。这很重要，因为PAR1调节了各种响应 细胞，包括感染和凋亡。在体外和体内，我们都发现PAR1抑制了炎症 破骨细胞生成反应，特别是由肿瘤坏死因子α（TNFα）刺激的反应，因为在PAR1中 细胞或小鼠对TNFα的反应显着增强。 PAR1对注射和细胞凋亡的许多抑制作用都是由酶介导的，激活了 蛋白C（APC）。最近，一组小分子，parmodulins被确定为选择性 PAR1的激动剂/拮抗剂。这些代理模仿APC的抗炎和抗凋亡作用，没有 影响其抗凝作用。在初步数据中，我们显示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蛋白合成或醇磷酸酶 活动。在此应用中，我们将检验以下假设，即parmodulins是一种潜在的新疗法 代谢骨疾病，可能具有更少的严重副作用。 在特定目标1中，我们将对ML-161和NRD-21的影响提供详细的分析 破骨细胞和成骨细胞的形成和功能。 在特定目标2中，我们将检查ML-161和NRD-21抑制炎症的体内能力 骨头对TNFα的反应。 如果成功，这些研究将为对的基础，以对 性类固醇戒断，衰老和炎症引起的鼠类疾病鼠模型的parmodulins 状况。