title: Loss of ATRX does not confer susceptibility to osteoarthritis.
abstract: The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adult skeleton in three different models of selective Atrx loss. We specifically targeted deletion of Atrx to the forelimb mesenchyme, to cartilage and to bone-forming osteoblasts. We previously demonstrated that loss of ATRX in forelimb mesenchyme causes brachydactyly while deletion in chondrocytes had minimal effects during development. We now show that targeted deletion of Atrx in osteoblasts causes minor dwarfism but does not recapitulate most of the skeletal phenotypes seen in ATR-X syndrome patients. In adult mice from all three models, we find that joints lacking Atrx are not more susceptible to osteoarthritis, as determined by OARSI scoring and immunohistochemistry. These results indicate that while ATRX plays limited roles during early stages of skeletal development, deficiency of the protein in adult tissues does not confer susceptibility to osteoarthritis.
authors.affiliation: Departments of Paediatrics and Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada ; Children's Health Research Institute, London, Ontario, Canada.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Solomon
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Bailey A
authors.initials: BA
authors.lastname: Russell
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Makar
authors.affiliation: Departments of Paediatrics and Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada ; Children's Health Research Institute, London, Ontario, Canada.
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
authors.affiliation: Children's Health Research Institute, London, Ontario, Canada ; Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D017353:Gene Deletion; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein