Biological Rhythms in the Intervertebral Disc: Implications for Homeostasis and Degeneration

Abstract

Biological rhythms temporally coordinate physiological and behavioural processes and are observed across taxa. Perhaps the best-known biological rhythm is the circadian rhythm. Circadian rhythms describe the ~24-hour rhythmic patterns seen in a multitude of cellular processes, acting through both central and peripheral molecular pacemakers. Chronic disruption to circadian rhythms (through ageing or chronic shift working) is thought to contribute to a multitude of diseases, including degenerative diseases of the musculoskeletal system. The intervertebral disc is known to possess an intrinsic circadian clock that drives downstream rhythmic gene transcription. These rhythmic outputs are thought to be essential for coping with the daily stresses that the intervertebral disc is exposed to within its unique physiological niche. Indeed, previous work has established an essential role for the circadian clock in murine intervertebral disc homeostasis. In this thesis, circadian clock disruption models are used to examine the importance of circadian clocks in the homeostasis and degeneration of the intervertebral disc. A novel ultradian transcriptional landscape is also discovered and incorporated into these studies. Profound age-related degeneration occurs within the intervertebral disc of the Col2a1-Bmal1 knockout mouse. A major osteogenic component to this phenotype is identified and appears to be linked to not only the loss of the circadian clock but also the emergence of a putative ultradian clock. Other aspects of intervertebral disc homeostasis, such as extracellular matrix microarchitecture and mitochondrial homeostasis, are shown to be disrupted within the annulus fibrosus of Bmal1 knockout mice. To support these findings, RNA-sequencing of dissected nucleus pulposus and annulus fibrosus tissue from mouse was carried out. This novel analysis allowed for a more accurate assessment of region- and tissue-type specific transcriptional changes related to time-of-day and mouse genotype (wildtype and Bmal1 knockout). Among the findings generated by this is an apparent loss of annulus fibrosus-like phenotype markers in Bmal1 knockout mice. The emergence of circadian rhythms in the developmental is then characterised to conclude, with data suggesting that the circadian clock is involved in not only pathological osteogenesis but also normal endochondral ossification during development. Collectively, these data highlight the relevance of biological rhythms in the maintenance of intervertebral disc homeostasis and identify potential molecular targets for augmenting intervertebral disc degeneration.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Judith Hoyland (Supervisor) & Qing-Jun Meng (Supervisor)