title: NFATc1 and NFATc2 repress spontaneous osteoarthritis.
abstract: Osteoarthritis (OA) was once viewed originally as a mechanical disease of "wear and tear," but advances made during the past two decades suggest that abnormal biomechanics contribute to active dysregulation of chondrocyte biology, leading to catabolism of the cartilage matrix. A number of signaling and transcriptional mechanisms have been studied in relation to the regulation of this catabolic program, but how they specifically regulate the initiation or progression of the disease is poorly understood. Here, we demonstrate that cartilage-specific ablation of Nuclear factor of activated T cells c1 (Nfatc1) in Nfatc2(-/-) mice leads to early onset, aggressive OA affecting multiple joints. This model recapitulates features of human OA, including loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and eventual progression to cartilage effacement and joint instability. Consistent with the notion that NFATC1 is an OA-suppressor gene, NFATC1 expression was significantly down-regulated in paired lesional vs. macroscopically normal cartilage samples from OA patients. The highly penetrant, early onset, and severe nature of this model make it an attractive platform for the preclinical development of treatments to alter the course of OA. Furthermore, these findings indicate that NFATs are key suppressors of OA, and regulating NFATs or their transcriptional targets in chondrocytes may lead to novel disease-modifying OA therapies.
authors.affiliation: Department of Pathology, Division of Rheumatology, Allergy and Immunology, Department of Medicine, and Department of Orthopedics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Greenblatt
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Ritter
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Kelly
authors.initials: K
authors.lastname: Tsang
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hu
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Antonios O
authors.initials: AO
authors.lastname: Aliprantis
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology* / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C494007:Nfatc2 protein, mouse