Mutations in Osteoprotegerin Cause Calcium Pyrophosphate Deposition Disease

护骨素突变导致焦磷酸钙沉积病

• 批准号: 10863809
• 负责人: Ann K Rosenthal
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10863809
• 关键词: Affect; Affinity; American; Amino Acids; Arthritis; Behavior; Binding; Biological Markers; Bone Density; Calcium Pyrophosphate; Calcium pyrophosphate deposition disease; Cell membrane; Cell surface; Characteristics; Chondrocytes; Chromatography; Clinical; Code; Crystal Formation; Data; Dimerization; Disease; Disease Clusterings; Elderly; Goals; Heparin Binding; Heparitin Sulfate; ICD-9; IGF1 gene; In Vitro; Ligands; Measures; Membrane; Molecular Abnormality; Molecular Sieve Chromatography; Mutation; NF-kappa B; Osteoblasts; Osteoclasts; Osteopenia; Pain; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Proteins; Publishing; Recombinants; Reporting; Risk Factors; Roentgen Rays; Role; Structure; Surface Plasmon Resonance; TNF-related apoptosis-inducing ligand; TNFRSF11B gene; TRANCE protein; Terminator Codon; Tissues; Transforming Growth Factor beta; Tumor necrosis factor receptor 11b; Veterans; Work; articular cartilage; dimer; disease phenotype; early onset; effective therapy; gain of function; gain of function mutation; in vivo Model; innovation; joint destruction; joint injury; kindred; loss of function; military veteran; new therapeutic target; novel therapeutics; older patient; osteoclastogenesis; premature; prevent; receptor; receptor binding; stem; subchondral bone

Calcium pyrophosphate deposition disease (CPDD) is a common type of arthritis defined by the presence of calcium pyrophosphate (CPP) crystals in articular cartilage. It is particularly common in the US Veteran population as risk factors for CPDD including advanced age and prior joint trauma are highly prevalent in American Veterans. We recently published a study of US veterans using ICD-9 codes to identify 29,000 American Veterans with the disease in a single 5-year period. While CPDD 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). The OPG mutation causing CPDD (mtOPG) results in an additional 19 amino acids added to the protein's C terminus near the heparin binding domain. OPG is decoy receptor for receptor activator of nuclear factor kappa B ligand (RANKL). RANKL promotes osteoclast formation, and because OPG blocks its function, reduction of OPG activity results in increased osteoclastogenesis. The phenotype of affected patients with this mutation includes exuberant CPP crystal formation, mild osteopenia and severe joint degeneration, a phenotype consistent with a loss of function of OPG. Indeed, preliminary data demonstrate that recombinant mtOPG displays inefficient inhibition of membrane-bound RANKL resulting in excess osteoclastogenesis in vitro. Interestingly, osteoclast conditioned media potently stimulates biomarkers of CPP crystal formation in chondrocytes. The purpose of this work is to investigate the conceptually innovative hypothesis that mtOPG produces CPDD by increasing osteoclastogenesis in subchondral bone. In specific aim 1, using in vitro and in vivo models, we will show that compared to wild type OPG (wtOPG), mtOPG ineffectively binds to the osteoblast cell membrane. resulting in excess un-opposed membrane-bound RANKL and increased osteoclast formation. Overabundant osteoclasts in subchondral bone produce joint damage and release CPP crystal-promoting factors into articular cartilage. In the second aim, structural studies using chromatography, surface plasmon resonance and small angle x-ray scattering, will demonstrate reduced affinity of mtOPG to bind heparan sulfate and decreased dimerization. The scientific premise of this work stems from careful observations of the phenotype of patients with the OPG mutation and is supported by preliminary in vitro functional studies of mtOPG. These studies are the first to identify the OPG/RANKL/RANK pathway in CPDD and to implicate subchondral bone as a target tissue in this disease. The shared clinical features of patients with CCAL1 and those with sporadic CPDD as well as the existence of available drugs which target this pathway make this work particularly exciting.

焦磷酸钙沉积病（CPDD）是一种常见的关节炎类型， 关节软骨中存在焦磷酸钙（CPP）晶体。显得尤为 在美国退伍军人人群中常见，是CPDD的风险因素，包括高龄和 先前的关节创伤在美国退伍军人中非常普遍。我们最近发表了一项研究， 美国退伍军人使用ICD-9代码识别29，000名美国退伍军人患有这种疾病， 单5年期。虽然CPDD以零星的方式影响老年患者， 过早地形成家族模式对这种疾病家族性形式的研究令人兴奋 机会，以确定新的治疗目标，目前无法治愈的关节炎。我们 最近证实，TNFRSF 11B终止密码子的突变导致早发性CPDD。 TNFRSF 11B是骨保护素（OPG）的编码。OPG突变导致CPDD（mtOPG） 导致在靠近肝素的蛋白质C末端添加额外的19个氨基酸 结合域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，由于OPG阻断其功能， OPG活性的降低导致破骨细胞生成增加。受影响的表型 具有这种突变的患者包括旺盛的CPP晶体形成，轻度骨质减少， 严重关节退行性变，与OPG功能丧失一致的表型。的确， 初步数据表明，重组mtOPG显示对 膜结合RANKL导致体外破骨细胞生成过量。有趣的是， 破骨细胞条件培养基有效地刺激CPP晶体形成的生物标志物， 软骨细胞这项工作的目的是调查概念创新 假设mtOPG通过增加破骨细胞生成产生CPDD， 软骨下骨在具体目标1中，使用体外和体内模型，我们将证明， 与野生型OPG（wtOPG）相比，mtOPG不能有效地与成骨细胞结合 膜的导致过量的非对抗性膜结合RANKL和破骨细胞增加 阵软骨下骨中过多的破骨细胞导致关节损伤和松解 CPP晶体促进因子进入关节软骨。在第二个目标中，结构研究使用 色谱，表面等离子体共振和小角X射线散射，将证明 mtOPG结合硫酸乙酰肝素的亲和力降低，二聚化减少。科学 这项工作的前提源于对OPG患者表型的仔细观察 突变，并得到mtOPG的初步体外功能研究的支持。这些研究 第一个在CPDD中识别OPG/RANKL/RANK通路并涉及软骨下骨 作为这种疾病的靶组织。CCAL 1患者和那些 散发性CPDD以及靶向该途径的可用药物的存在使得 这项工作特别令人兴奋。

项目成果

Calcium pyrophosphate deposition and crowned dens syndrome.

焦磷酸钙沉积和冠齿综合征。

• DOI: 10.3949/ccjm.88a.21008
• 发表时间: 2021
• 期刊: Cleveland Clinic journal of medicine
• 影响因子: 6.1
• 作者: Rosenthal,AnnK

Towards development of core domain sets for short term and long term studies of calcium pyrophosphate crystal deposition (CPPD) disease: A framework paper by the OMERACT CPPD working group.

• DOI: 10.1016/j.semarthrit.2021.04.019
• 发表时间: 2021-08
• 期刊: Seminars in arthritis and rheumatism
• 影响因子: 5
• 作者: Cai K;Fuller A;Zhang Y;Hensey O;Grossberg D;Christensen R;Shea B;Singh JA;McCarthy GM;Rosenthal AK;Filippou G;Taylor WJ;Diaz-Torne C;Stamp LK;Edwards NL;Pascart T;Becce F;Nielsen SM;Tugwell P;Beaton D;Abhishek A;Tedeschi SK;Dalbeth N
• 通讯作者: Dalbeth N

Calcium pyrophosphate crystal size and characteristics.

• DOI: 10.1016/j.ocarto.2020.100133
• 发表时间: 2021-03-01
• 期刊: Osteoarthritis and cartilage open
• 作者: Zell, Monica;Aung, Thanda;FitzGerald, John D
• 通讯作者: FitzGerald, John D