Molecular pathways of calcium pyrophosphate deposition disease

焦磷酸钙沉积病的分子途径

• 批准号: 10463447
• 负责人: Gabriel Mbalaviele
• 金额: $ 49.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463447
• 关键词: Adult; Affect; Age; Alkaline Phosphatase; American; Amino Acids; Animal Model; Arthritis; Back; CRISPR/Cas technology; Calcium Pyrophosphate; Calcium pyrophosphate deposition disease; Cartilage; Chondrocytes; Clinical; Code; Conditioned Culture Media; Crystal Formation; Crystallization; Data; Development; Diphosphates; Disease; Early identification; Elderly; Exhibits; Feedback; Genetically Engineered Mouse; Goals; Human; In Vitro; Individual; Induced Mutation; Injury; Joints; Knock-in Mouse; Lead; Mediating; Molecular; Molecular Abnormality; Mus; Mutation; NF-kappa B; Osteoblasts; Osteoclasts; Osteopenia; Pain; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Pre-Clinical Model; Process; Production; Proteins; Public Health; Publishing; Receptor Inhibition; Recombinants; Reporting; Risk Factors; Role; Source; TNFRSF11B gene; TRANCE protein; Tail; Terminator Codon; Tissues; Translations; Tumor necrosis factor receptor 11b; Work; age related; articular cartilage; base; bone; bone mass; drug development; early onset; effective therapy; extracellular; genetic manipulation; in vivo Model; innovation; joint injury; kindred; loss of function; mouse model; mutant; new therapeutic target; novel; novel therapeutics; older patient; osteoclastogenesis; phosphoric diester hydrolase; preclinical study; premature; prevent; pyrophosphatase; receptor; receptor binding; stem; subchondral bone; theories; therapeutic target

Calcium pyrophosphate deposition disease (CPDD) is a common type of arthritis defined by the presence of calcium pyrophosphate (CPP) crystals in articular cartilage. While CPDD typically affects elderly patients in a sporadic fashion, it also occurs prematurely in familial patterns. Studies of familial forms of this disease present exciting opportunities to identify novel therapeutic targets for this currently untreatable arthritis. We recently confirmed that a mutation in the stop codon of TNFRSF11B causes early onset CPDD. TNFRSF11B codes for osteoprotegerin (OPG). OPG is a decoy receptor for Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL). RANKL promotes osteoclast formation. Our preliminary data clearly demonstrate that recombinant mutant OPG (OPGmt) displays inefficient inhibition of RANKL resulting in excess osteoclastogenesis in vitro. Our genetically engineered mice carrying OPGmt have osteopenia and premature arthritis mirroring the effects of OPGmt in humans. We have also found that osteoclast conditioned media potently stimulates chondrocyte pyrophosphate (PPi) production, a necessary process for CPP crystal formation. The purpose of this work is to investigate the conceptually innovative hypothesis that OPGmt produces CPDD by increasing osteoclastogenesis in subchondral bone. We propose that excess osteoclasts in subchondral bone stimulate cartilage PPi production and that high cartilage-derived PPi levels target pre-osteoblasts to exaggerate subchondral osteoclastogenesis seen in the presence of OPGmt. The scientific premise of this work stems from careful observations of the phenotype of patients with OPGmt and strong preliminary data. In Aim 1 we will use Opgmt/+ and Opgmt/mt knock-in mice to comprehensively determine the role of Opgmt in arthritis pathogenesis in mice and determine if disease can be prevented by blocking RANKL. In Aim 2, we will employ in vitro and in vivo models to investigate the role of high PPi levels in promoting OPGmt-induced arthritis and elucidate the underlying mechanisms. This work is the first to identify the OPG/RANKL/RANK pathway in CPDD and to implicate subchondral bone as a primary target tissue in this disease. This proposal includes a novel mouse model that will serve as the basis for further mechanistic and pre-clinical studies in CPDD. The shared clinical features of patients with the OPG mutation and those with age-related CPDD and the existence of available drugs which target these pathways support rapid translation of this work.

焦磷酸钙沉积疾病（CPDD）是由存在的一种常见关节炎类型 关节软骨中的焦磷酸钙（CPP）晶体。虽然CPDD通常会影响老年患者 零星的时尚，它也以家族模式过早发生。有关这种疾病的家族形式的研究 令人兴奋的机会来确定目前无法治疗的关节炎的新型治疗靶标。我们最近 确认TNFRSF11b的终止密码子中的突变会引起早期发作CPDD。 TNFRSF11b代码 骨蛋白酶（OPG）。 OPG是核因子Kappa B配体受体激活剂的诱饵受体 （RANKL）。 RANKL促进破骨细胞的形成。我们的初步数据清楚地表明了重组 突变OPG（OPGMT）表现出对RANKL的效率低​​下，导致体外过量破骨细胞生成。我们的 携带OPGMT的基因工程小鼠患有骨质减少症和早产关节炎，反映了 人类的opgmt。我们还发现，破骨细胞培养基有效刺激软骨细胞 焦磷酸（PPI）生产，这是CPP晶体形成的必要过程。这项工作的目的是 调查OPGMT通过增加而产生CPDD的概念上创新的假设 软骨下骨的破骨细胞生成。我们提出，在软骨下骨中过多的破骨细胞刺激 软骨PPI产生和高软骨衍生的PPI水平的目标固定细胞夸大 在OPGMT存在下可见的软骨下骨构成。这项工作的科学前提源于 仔细观察OPGMT患者和强大初步数据的表型。在AIM 1中，我们将使用 OPGMT/+和OPGMT/MT敲击小鼠，以全面确定OPGMT在关节炎发病机理中的作用 小鼠并确定是否可以通过阻塞RANKL来预防疾病。在AIM 2中，我们将在体外和 体内模型研究高PPI水平在促进OPGMT诱导的关节炎中的作用并阐明 基本机制。这项工作是第一个识别CPDD中的OPG/RANKL/RANC途径的工作 在这种疾病中暗示了软骨下骨作为主要目标组织。该提议包括一只新颖的鼠标 将作为CPDD进一步机械和临床前研究的基础的模型。共同的临床 具有OPG突变的患者和与年龄相关的CPDD的患者的特征 针对这些途径的药物支持这项工作的快速翻译。