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： 目前对于代谢性骨疾病的治疗是有效的。然而，它们的使用与罕见的 但副作用较大，限制了患者的接受度。使用最广泛的药物， 双膦酸盐和狄诺塞麦抑制吸收和形成，这种双重作用可能导致 严重并发症的发生（颌骨坏死和转子下骨折）。所以， 迫切需要针对这些疾病的有效且降低风险的新疗法 并发症，将更容易被患者接受。抑制吸收和抑制药物的鉴定 要么没有效果，要么刺激形成对于寻找副作用更少的疗法可能至关重要。 众所周知，炎症是类风湿等代谢性骨病的重要组成部分 关节炎、炎症性肠病和牛皮癣，还有骨质疏松症和佩吉特氏病。我们有 发现破骨细胞前体细胞在其增殖过程中短暂表达蛋白酶激活受体 1 (PAR1) 分化为成熟的破骨细胞。这很重要，因为 PAR1 调节多种反应 细胞，包括炎症和细胞凋亡。在体外和体内我们发现 PAR1 抑制炎症 破骨细胞生成反应，特别是 PAR1 以来由肿瘤坏死因子 α (TNFα) 刺激的破骨细胞反应 缺陷细胞或小鼠对 TNFα 的反应明显增强。 PAR1 对炎症和细胞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 被鉴定为具有选择性 PAR1 的激动剂/拮抗剂。这些药物模仿 APC 的抗炎和抗凋亡作用，但无需 影响其抗凝作用。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。在此应用中，我们将测试帕莫杜林是一种潜在的新疗法的假设 代谢性骨疾病，其严重副作用可能较少。 在具体目标1中，我们将详细分析ML-161和NRD-21对体外的影响 破骨细胞和成骨细胞的形成和功能。 在具体目标 2 中，我们将检查 ML-161 和 NRD-21 抑制炎症的体内能力 骨对 TNFα 的反应。 如果成功，这些研究将为更详细的影响研究奠定基础 Parmodulins 对因性类固醇戒断、衰老和炎症引起的骨病小鼠模型的影响 状况。