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Extended report
A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis
  1. Yolande F M Ramos1,2,
  2. Steffan D Bos1,2,
  3. Ruud van der Breggen1,
  4. Margreet Kloppenburg3,
  5. Kai Ye1,
  6. Eric-Wubbo E M W Lameijer1,
  7. Rob G H H Nelissen4,
  8. P Eline Slagboom1,2,
  9. Ingrid Meulenbelt1,2
  1. 1Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
  3. 3Department of Rheumatology & Department of Clinical Epidemiology, Leiden, The Netherlands
  4. 4Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Ingrid Meulenbelt, Department of Molecular Epidemiology, Leiden University Medical Center, LUMC Postzone S-05-P, PO Box 9600, Leiden 2300 RC, The Netherlands; i.meulenbelt{at}


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.

  • Osteoarthritis
  • Chondrocalcinosis
  • Epidemiology

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