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

Dudek, Michal; Morris, Honor; Rogers, Natalie; Pathiranage, Dharshika; Raj, Simpy; Chan, D; Kadler, Karl E.; Hoyland, Judith A.; Meng, Qing‐Jun

doi:10.1016/j.matbio.2023.07.002

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…This is in line with our previous work showing that ablation of Bmal1 using the same Col6a1 -cre driver in C57BL/6J mice results in joint stiffening 3 . Bmal1 ablation in other tissue contexts has also been shown to alter ECM organisation 62,63 . Together these findings reveal a role for FLS BMAL1 activity or wider circadian clock function in shaping joint ECM dynamics, and we speculate that altered collagen expression and/or resulting joint architecture contribute to the attenuated susceptibility to CIA observed here.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast-like synoviocytes orchestrate daily rhythmic inflammation in arthritis

Downton,

Dickson,

Ray

et al. 2024

Preprint

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Rheumatoid arthritis is a chronic inflammatory disease that shows characteristic diurnal variation in symptom severity, where joint resident fibroblast-like synoviocytes (FLS) act as important mediators of arthritis pathology. We investigate the role of FLS circadian clock function in directing rhythmic joint inflammation in a murine model of inflammatory arthritis. We demonstrate FLS time of day-dependent gene expression is attenuated in arthritic joints, except for a subset of disease-modifying genes. Deletion of essential clock gene Bmal1 in FLS reduced susceptibility to collagen-induced arthritis (CIA), but did not impact symptomatic severity in affected mice. Notably, FLS Bmal1 deletion resulted in loss of diurnal expression of disease-modulating genes across the joint, and elevated production of MMP3, a prognostic marker of joint damage in inflammatory arthritis. This work identifies the FLS circadian clock as an influential driver of daily oscillations in joint inflammation, and a potential regulator of destructive pathology in chronic inflammatory arthritis.

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Section: Discussionmentioning

confidence: 99%

Fibroblast-like synoviocytes orchestrate daily rhythmic inflammation in arthritis

Downton,

Dickson,

Ray

et al. 2024

Preprint

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“… 86 – 88 The cell signaling pathways regulated by circadian rhythms become increasingly dysregulated with advancing age and these pathways include genes that regulate both extracellular matrix gene expression and its assembly. 87 , 89 – 91 …”

Section: Discussionmentioning

confidence: 99%

Age-Related Differences in the Mouse Corneal Epithelial Transcriptome and Their Impact on Corneal Wound Healing

Abu-Romman,

Scholand,

Govindarajan

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose Aging is a risk factor for dry eye. We sought to identify changes in the aged mouse corneal epithelial transcriptome and determine how age affects corneal sensitivity, re-epithelialization, and barrier reformation after corneal debridement. Methods Corneal epithelium of female C57BL/6J (B6) mice of different ages (2, 12, 18, and 24 months) was collected, RNA extracted, and bulk RNA sequencing performed. Cornea sensitivity was measured with an esthesiometer in 2- to 3-month-old, 12- to 13-month-old, 18- to 19-month-old, and 22- to 25-month-old female and male mice. The 2-month-old and 18-month-old female and male mice underwent unilateral corneal debridement using a blunt blade. Wound size and fluorescein staining were visualized and photographed at different time points, and a re-epithelialization rate curve was calculated. Results There were 157 differentially expressed genes in aged mice compared with young mice. Several pathways downregulated with age control cell migration, proteoglycan synthesis, and collagen trimerization, assembly, biosynthesis, and degradation. Male mice had decreased corneal sensitivity compared with female mice at 12 and 24 months of age. Aged mice, irrespective of sex, had delayed corneal re-epithelialization in the first 48 hours and worse corneal fluorescein staining intensity at day 14 than young mice. Conclusions Aged corneal epithelium has an altered transcriptome. Aged mice regardless of sex heal more slowly and displayed more signs of corneal epithelial defects after wounding than young mice. These results indicate that aging significantly alters the corneal epithelium and its ability to coordinate healing.

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“…Interestingly, there was another downregulated theme that contained the entity Rorα, RAR-related orphan receptor alpha, known to be a major circadian clock gene. We have shown that there is an interaction between BMAL1 and RORα and they modulate HIF-1α activity as well as ECM homeostasis and perturbation in circadian clock genes results in disc degeneration ( Suyama et al, 2016 ; Dudek et al, 2017 ; Wang et al, 2022 ; Dudek et al, 2023 ). Notably, corroborating our current findings, HIF-2α FoxA2Cre mouse has shown upregulation in circadian clock pathways.…”

Section: Discussionmentioning

confidence: 99%

Increased HIF-2α activity in the nucleus pulposus causes intervertebral disc degeneration in the aging mouse spine

Johnston,

Tsingas,

Ain

et al. 2024

Front. Cell Dev. Biol.

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Hypoxia-inducible factors (HIFs) are essential to the homeostasis of hypoxic tissues. Although HIF-2α, is expressed in nucleus pulposus (NP) cells, consequences of elevated HIF-2 activity on disc health remains unknown. We expressed HIF-2α with proline to alanine substitutions (P405A; P531A) in the Oxygen-dependent degradation domain (HIF-2αdPA) in the NP tissue using an inducible, nucleus pulposus-specific K19CreERT allele to study HIF-2α function in the adult intervertebral disc. Expression of HIF-2α in NP impacted disc morphology, as evident from small but significantly higher scores of degeneration in NP of 24-month-old K19CreERT; HIF-2αdPA (K19-dPA) mice. Noteworthy, comparisons of grades within each genotype between 14 months and 24 months indicated that HIF-2α overexpression contributed to more pronounced changes than aging alone. The annulus fibrosus (AF) compartment in the 14-month-old K19-dPA mice exhibited lower collagen turnover and Fourier transform-infrared (FTIR) spectroscopic imaging analyses showed changes in the biochemical composition of the 14- and 24-month-old K19-dPA mice. Moreover, there were changes in aggrecan, chondroitin sulfate, and COMP abundance without alterations in NP phenotypic marker CA3, suggesting the overexpression of HIF-2α had some impact on matrix composition but not the cell phenotype. Mechanistically, the global transcriptomic analysis showed enrichment of differentially expressed genes in themes closely related to NP cell function such as cilia, SLIT/ROBO pathway, and HIF/Hypoxia signaling at both 14- and 24-month. Together, these findings underscore the role of HIF-2α in the pathogenesis of disc degeneration in the aged spine.

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

Cited by 11 publications

References 48 publications

Fibroblast-like synoviocytes orchestrate daily rhythmic inflammation in arthritis

Fibroblast-like synoviocytes orchestrate daily rhythmic inflammation in arthritis

Age-Related Differences in the Mouse Corneal Epithelial Transcriptome and Their Impact on Corneal Wound Healing

Increased HIF-2α activity in the nucleus pulposus causes intervertebral disc degeneration in the aging mouse spine

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