Yolande F M Ramos1, Steffan D Bos1, Ruud van der Breggen2, Margreet Kloppenburg3, Kai Ye2, Eric-Wubbo E M W Lameijer2, Rob G H H Nelissen4, P Eline Slagboom1, Ingrid Meulenbelt1. 1. Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands. 2. Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3. Department of Rheumatology & Department of Clinical Epidemiology, Leiden, The Netherlands. 4. Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: C J Williams; U Qazi; M Bernstein; A Charniak; C Gohr; E Mitton-Fitzgerald; A Ortiz; L Cardinal; A T Kaell; A K Rosenthal Journal: Osteoarthritis Cartilage Date: 2018-03-22 Impact factor: 6.576
Authors: Michael J Jurynec; Catherine M Gavile; Matthew Honeggar; Ying Ma; Shivakumar R Veerabhadraiah; Kendra A Novak; Kazuyuki Hoshijima; Nikolas H Kazmers; David J Grunwald Journal: Ann Rheum Dis Date: 2022-06-22 Impact factor: 27.973
Authors: Catherine M Gavile; Nikolas H Kazmers; Kendra A Novak; Huong D Meeks; Zhe Yu; Joy L Thomas; Channing Hansen; Tyler Barker; Michael J Jurynec Journal: J Hand Surg Am Date: 2022-09-29 Impact factor: 2.342
Authors: Nobuaki Chinzei; Muhammad Farooq Rai; Shingo Hashimoto; Eric J Schmidt; Ken Takebe; James M Cheverud; Linda J Sandell Journal: Arthritis Rheumatol Date: 2019-01-25 Impact factor: 10.995
Authors: Nikolas H Kazmers; Huong D Meeks; Kendra A Novak; Zhe Yu; Gail L Fulde; Joy L Thomas; Tyler Barker; Michael J Jurynec Journal: Arthritis Rheumatol Date: 2021-01-29 Impact factor: 10.995
Authors: Elizabeth Mitton-Fitzgerald; Claudia M Gohr; Charlene J Williams; Amaryllis Ortiz; Gabriel Mbalaviele; Ann K Rosenthal Journal: Arthritis Rheumatol Date: 2021-06-08 Impact factor: 15.483