title: The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.
abstract: Osteoarthritis (OA) is the most prevalent and debilitating joint disease, and there are currently no effective disease-modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage and loss of articular cartilage. Autonomous circadian clocks have been identified in mouse cartilage, and environmental disruption of circadian rhythms in mice predisposes animals to OA-like damage. However, the contribution of the cartilage clock mechanisms to the maintenance of tissue homeostasis is still unclear. Here, we have shown that expression of the core clock transcription factor BMAL1 is disrupted in human OA cartilage and in aged mouse cartilage. Furthermore, targeted Bmal1 ablation in mouse chondrocytes abolished their circadian rhythm and caused progressive degeneration of articular cartilage. We determined that BMAL1 directs the circadian expression of many genes implicated in cartilage homeostasis, including those involved in catabolic, anabolic, and apoptotic pathways. Loss of BMAL1 reduced the levels of phosphorylated SMAD2/3 (p-SMAD2/3) and NFATC2 and decreased expression of the major matrix-related genes Sox9, Acan, and Col2a1, but increased p-SMAD1/5 levels. Together, these results define a regulatory mechanism that links chondrocyte BMAL1 to the maintenance and repair of cartilage and suggest that circadian rhythm disruption is a risk factor for joint diseases such as OA.
authors.forename: Michal
authors.initials: M
authors.lastname: Dudek
authors.forename: Nicole
authors.initials: N
authors.lastname: Gossan
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
authors.forename: Jayalath P D
authors.initials: JP
authors.lastname: Ruckshanthi
authors.forename: Hikari
authors.initials: H
authors.lastname: Yoshitane
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Ding
authors.initials: D
authors.lastname: Jin
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Maya
authors.initials: M
authors.lastname: Boudiffa
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellantuono
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fukada
authors.forename: Ray P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Meng
mesh_terms: D056930:ARNTL Transcription Factors / Q000032:analysis / Q000502:physiology*; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D019902:Chondrocytes / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000502:physiology; D010003:Osteoarthritis / Q000209:etiology*; D017423:Sequence Analysis, RNA; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D050778:NFATC Transcription Factors; D016212:Transforming Growth Factor beta