期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 74, 期 9, 页码 1756-1762出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2013-205149
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类别
资金
- European Union [259679]
- Dutch Arthritis Association (Reumafonds)
- Pfizer Inc., Groton, CT, USA
- Leiden University Medical Centre (LUMC)
- Reumafonds [DAA 10-1-402, DAA 101-402]
- Netherlands Organization of Scientific Research (NWO) [MW 904-61-095, 911-03-016, 917 66344, 911-03-012]
- LUMC
- Centre of Medical System Biology (CMSB)
- Netherlands Consortium for Healthy Aging (NCHA)
- Innovation-Oriented Research Program on Genomics [SenterNovem IGE05007]
- NWO
- CMSB [050-060-810]
- NCHA [050-060-810]
- CMSB
- NCHA
- BBMRI-NL - Dutch government [NWO 184.021.007]
Objective To identify pathogenic mutations that reveal underlying biological mechanisms driving osteoarthritis (OA). Methods 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. Results 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. Conclusions 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.
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