title: A gain of function mutation in TNFRSF11B encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis.
abstract: 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.
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors.forename: Yolande F M
authors.initials: YF
authors.lastname: Ramos
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors.forename: Steffan D
authors.initials: SD
authors.lastname: Bos
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.affiliation: Department of Rheumatology & Department of Clinical Epidemiology, Leiden, The Netherlands.
authors.forename: Margreet
authors.initials: M
authors.lastname: Kloppenburg
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Eric-Wubbo E M W
authors.initials: EW
authors.lastname: Lameijer
authors.affiliation: Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rob G H H
authors.initials: RG
authors.lastname: Nelissen
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001862:Bone Resorption / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002805:Chondrocalcinosis / Q000150:complications / Q000235:genetics*; D059472:Exome; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010003:Osteoarthritis / Q000150:complications / Q000235:genetics*; D010010:Osteoclasts; D053244:Osteoprotegerin / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human
keywords: Chondrocalcinosis; Epidemiology; Osteoarthritis