Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Ann Rheum Dis. 2015 Sep;74(9):1756-62. doi: 10.1136/annrheumdis-2013-205149. Epub 2014 Apr 17.
To identify pathogenic mutations that reveal underlying biological mechanisms driving osteoarthritis (OA).
Exome sequencing was applied to two distant family members with dominantly inherited early onset primary OA at multiple joint sites with chondrocalcinosis (familial generalised osteoarthritis, FOA). Confirmation of mutations occurred by genotyping and linkage analyses across the extended family. The functional effect of the mutation was investigated by means of a cell-based assay. To explore generalisability, mRNA expression analysis of the relevant genes in the discovered pathway was explored in preserved and osteoarthritic articular cartilage of independent patients undergoing joint replacement surgery.
We identified a heterozygous, probably damaging, read-through mutation (c.1205A=>T; p.Stop402Leu) in TNFRSF11B encoding osteoprotegerin that is likely causal to the OA phenotype in the extended family. In a bone resorption assay, the mutant form of osteoprotegerin showed enhanced capacity to inhibit osteoclastogenesis and bone resorption. Expression analyses in preserved and affected articular cartilage of independent OA patients showed that upregulation of TNFRSF11B is a general phenomenon in the pathophysiological process.
Albeit that the role of the molecular pathway of osteoprotegerin has been studied in OA, we are the first to demonstrate that enhanced osteoprotegerin function could be a directly underlying cause. We advocate that agents counteracting the function of osteoprotegerin could comply with new therapeutic interventions of OA.
鉴定导致骨关节炎（OA）的潜在生物学机制的致病突变。
对两个具有显性遗传、早发性多关节部位骨关节炎伴软骨钙质沉着症（家族性广泛性骨关节炎，FOA）的远亲家族成员进行外显子组测序。通过对扩展家族的基因分型和连锁分析确认突变的发生。通过细胞测定法研究突变的功能效应。为了探索普遍性，对接受关节置换手术的独立患者的关节软骨中发现途径的相关基因的 mRNA 表达分析进行了探讨。
我们在编码骨保护素的 TNFRSF11B 中鉴定出一个杂合的、可能具有破坏性的通读突变（c.1205A=>T；p.Stop402Leu），该突变可能是家族中 OA 表型的原因。在骨吸收测定中，突变型骨保护素显示出增强抑制破骨细胞生成和骨吸收的能力。对独立 OA 患者的保存和受影响的关节软骨进行的表达分析表明，TNFRSF11B 的上调是病理生理过程中的普遍现象。
尽管骨保护素分子途径的作用已在 OA 中进行了研究，但我们是第一个证明增强的骨保护素功能可能是直接的潜在原因。我们主张，拮抗骨保护素功能的药物可能符合 OA 的新治疗干预措施。
