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，其定义为 关节软骨中的焦磷酸钙(CPP)晶体。而慢性阻塞性肺疾病通常会影响老年患者 除了零星的时尚外，它还过早地出现在家族模式中。目前对这种疾病的家族性形式的研究 为这一目前无法治愈的关节炎确定新的治疗目标的令人兴奋的机会。我们最近 证实TNFRSF11B终止密码子突变导致早发性CPDD。TNFRSF11B代码 骨保护素(OPG)。OPG是核因子-kappaB受体激活剂的诱骗受体 (RANKL)。RANKL促进破骨细胞形成。我们的初步数据清楚地表明，重组 突变型OPG(OPGmt)在体外对RANKL的抑制效果不佳，导致破骨细胞过度生成。我们的 携带OPGmt的基因工程小鼠有骨量减少和过早关节炎，这反映了OPGmt的影响 OPGmt在人类中的表达。我们还发现破骨细胞条件培养液可以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 研究概念创新假说，即OPGmt通过增加 软骨下骨中破骨细胞的形成。我们认为软骨下骨中过多的破骨细胞会刺激 软骨PPI的产生和软骨来源的高PPI水平以成骨前细胞为靶点来夸大 在OPGmt存在下可见软骨下破骨细胞形成。这项工作的科学前提源于 仔细观察OPGmt患者的表型，有较强的初步数据。在目标1中，我们将使用 Opgmt/+和Opgmt/mt敲入小鼠全面确定Opgmt在关节炎发病机制中的作用 并确定是否可以通过阻断RANKL来预防疾病。在目标2中，我们将在体外和在 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 潜在的机制。这项工作首次发现了CPDD中OPG/RANKL/RANK通路，并 牵涉到软骨下骨作为本病的主要靶组织。这项提议包括一种新的鼠标 该模型将作为CPDD进一步的机械性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患者的特点及其存在的可利用的 针对这些途径的药物支持这项工作的快速翻译。

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.