Molecular pathways of calcium pyrophosphate deposition disease

焦磷酸钙沉积病（CPDD）是一种常见的关节炎类型， 焦磷酸钙（CPP）晶体在关节软骨。虽然CPDD通常影响老年患者， 虽然是零星的，但它也会以家族模式过早发生。对这种疾病的家族形式的研究表明， 为目前无法治愈的关节炎确定新的治疗靶点提供了令人兴奋的机会。我们最近 证实了TNFRSF 11B终止密码子的突变导致早发性CPDD。TNFRSF 11B代码 骨保护素（OPG）。OPG是核因子κ B配体受体激活剂的诱饵受体 （RANKL）。RANKL促进破骨细胞形成。我们的初步数据清楚地表明， 突变型OPG（OPGmt）在体外表现出对RANKL的无效抑制，导致过量的破骨细胞生成。我们 携带OPGmt的基因工程小鼠出现骨质减少和过早关节炎， 人体OPGmt。我们还发现破骨细胞条件培养基有效地刺激软骨细胞， 焦磷酸盐（PPi）的生产是CPP晶体形成的必要过程。这项工作的目的是 调查概念上的创新假设，即OPGmt通过增加 软骨下骨中的破骨细胞生成。我们认为，软骨下骨中过量的破骨细胞刺激了 软骨PPi产生和高软骨来源的PPi水平靶向前成骨细胞， 存在OPGmt时观察到的软骨下破骨细胞生成。这项工作的科学前提源于 对OPGmt患者表型的仔细观察和强有力的初步数据。在目标1中，我们将使用 本研究采用Opgmt/+和Opgmt/mt基因敲入小鼠，以全面确定Opgmt在关节炎发病机制中的作用。 小鼠，并确定是否可以通过阻断RANKL来预防疾病。在目标2中，我们将在体外和体内 体内模型，以研究高PPi水平在促进OPGmt诱导的关节炎中的作用，并阐明 基本机制。这项工作是第一个确定OPG/RANKL/RANK通路在CPDD和 表明软骨下骨是这种疾病主要靶组织。该提案包括一种新颖的鼠标 该模型将作为进一步的机制和临床前研究的基础。共享临床 OPG突变患者和年龄相关性CPDD患者的特征以及是否存在可用的 靶向这些途径的药物支持这项工作的快速转化。

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.