The clock transcription factor BMAL1 is a key regulator of extracellular matrix homeostasis and cell fate in the intervertebral disc

• DOI: 10.1101/2023.02.12.528214
• Publication Date: 2023-02-13T03:35:10Z
• Authors: Michal Dudek; Honor Morris; Natalie Rogers; Dharshika RJ Path...; Danny Chan; Karl E Kadler; Judith Hoyland; Qing-Jun Meng
• Keywords: Knockout mouse; FOXO1

Abstract The circadian clock in mammals temporally coordinates physiological and behavioural processes to anticipate daily rhythmic changes their environment. Chronic disruption rhythms (e.g., through ageing or shift work) is thought contribute a multitude of diseases, including degeneration the musculoskeletal system. intervertebral disc (IVD) spine contains clocks which control ∼6% transcriptome manner, key genes involved extracellular matrix (ECM) homeostasis. However, it remains largely unknown what extent local IVD molecular required drive gene transcription physiology. In this work, we identified profound age-related ECM microarchitecture an endochondral ossification-like phenotype annulus fibrosus (AF) region Col2a1 - Bmal1 knockout mice. Circadian time series RNA-Seq whole revealed loss patterns expression, with unexpected emergence 12-hour ultradian rhythms, FOXO factors. Further RNA sequencing AF tissue region-specific evidencing markers dysregulation pathways Consistent up-regulation FOXO1 mRNA protein levels IVDs, inhibition cells suppressed osteogenic differentiation. Collectively, these data highlight importance mechanism maintenance cell fate homeostasis IVD. studies may identify potential new targets for alleviating degeneration.