Chapter 6 A gain of function mutation in TNFRSF 11 B causes osteoarthritis with chondrocalcinosis

Objective To identify pathogenic mutations that reveal underlying biological mechanisms driving OA. Methods Exome sequencing was applied to two distant family members with dominantly inherited early onset primary osteoarthritis at multiple joint sites with chondrocalcinosis (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 generalizability, 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 osteoarthritis 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 osteoarthritis patients showed that up-regulation 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 osteoarthritis, 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 osteoarthritis.