A matter of time: Circadian clocks in osteoarthritis and the potential of chronotherapy

Dernie, Francesco; Adeyoju, Daniel

doi:10.1016/j.exger.2020.111163

Cited by 13 publications

(14 citation statements)

References 139 publications

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“…expression of BMAL1 was progressively reduced in human OA cartilage with upgrading severity, and cartilage-specific ablation of Bmal1 in mouse caused progressive degeneration of articular cartilage. The reduced expression of BMAL1, reflecting dampened peripheral clocks, in human OA samples has been consistently observed in many other reports [1,2]. In line with the pivotal roles of BMAL1 in cartilage homeostasis, degradation of cartilage was also present in the Clock Δ19 mutant mice due to upregulated inflammatory activity [4].…”

Section: Introductionsupporting

confidence: 72%

“…Mounting evidence has linked clock functions to multiple facets of cartilage homeostasis and degeneration, placing the circadian clock in a central role in both osteoarthritis (OA) pathology and therapeutic development [1,2]. The core clock component brain and muscle ARNT-like 1 (BMAL1) and its heterodimerization partner circadian locomotor output cycles kaput (CLOCK) are essential for both the master clock in the suprachiasmatic nucleus and peripheral circadian clocks present in tissues outside the brain, such as cartilage [2]. Notably, BMAL1 and CLOCK are decisively engaged in cartilage degeneration.…”

Section: Introductionmentioning

confidence: 99%

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Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration

Pang

Wang

et al. 2022

The FEBS Journal

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Dampened peripheral clocks have been linked to osteoarthritis (OA), yet it is unclear whether drugging the clock can ameliorate OA. Given that RORs and REV-ERBs mediate respectively, positive and negative transcriptional feedback of the master clock gene BMAL1, we investigate whether RORs agonist Nobiletin (NOB) and SR1078, and REV-ERBs antagonist SR8278 can enhance BMAL1 expression and attenuate cartilage degeneration. NOB and SR8278 promoted BMAL1 expression and elicited mitigating effects against IL-1β-induced degeneration of cartilage explants, as evidenced by increased cellular density and collagen synthesis along with alleviated catabolism and collagen denaturation. Despite promoted BMAL1 expression, SR1078 concomitantly suppressed chondrocyte anabolism and catabolism. Consistent with these findings, NOB and SR8278 treatment, but not SR1078, effectively attenuated structural destruction of articular cartilage in surgery-induced OA mouse models. Notably, the beneficial effects of NOB and SR8278 were evidently observed in IL-1βinduced degeneration of human cartilage explants and immortalized human chondrocytes. Moreover, BMAL1 knockdown assays indicated that NOB and SR8278 enhanced clock function and concordantly rendered protection against altered anabolism and catabolism in a BMAL1-dependent regime. Collectively, our study suggests that targeting RORs and REV-ERBs to promote the dampened peripheral clocks could be a route taken to apply chronotherapy within the context of OA.

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Section: Introductionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration

Pang

Wang

et al. 2022

The FEBS Journal

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“…SIRT1 is involved in both osteogenesis and positive regulation of Clock. While crosstalk between chondrogenesis and the circadian clock through SIRT1 has been established [ 176 ], this is yet to be ascertained in osteogenesis. CLOCK mediated acetylation of BMAL1 at Lys537 through its acetylase activity, facilitating recruitment of CRY1 [ 177 ].…”

Section: Environmental Cues Regulating Osteogenesismentioning

confidence: 99%

Regulation and Role of Transcription Factors in Osteogenesis

Chan

Tan

et al. 2021

IJMS

141

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Bone is a dynamic tissue constantly responding to environmental changes such as nutritional and mechanical stress. Bone homeostasis in adult life is maintained through bone remodeling, a controlled and balanced process between bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoblasts secrete matrix, with some being buried within the newly formed bone, and differentiate to osteocytes. During embryogenesis, bones are formed through intramembraneous or endochondral ossification. The former involves a direct differentiation of mesenchymal progenitor to osteoblasts, and the latter is through a cartilage template that is subsequently converted to bone. Advances in lineage tracing, cell sorting, and single-cell transcriptome studies have enabled new discoveries of gene regulation, and new populations of skeletal stem cells in multiple niches, including the cartilage growth plate, chondro-osseous junction, bone, and bone marrow, in embryonic development and postnatal life. Osteoblast differentiation is regulated by a master transcription factor RUNX2 and other factors such as OSX/SP7 and ATF4. Developmental and environmental cues affect the transcriptional activities of osteoblasts from lineage commitment to differentiation at multiple levels, fine-tuned with the involvement of co-factors, microRNAs, epigenetics, systemic factors, circadian rhythm, and the microenvironments. In this review, we will discuss these topics in relation to transcriptional controls in osteogenesis.

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“…Disruption to this balance, for example, through increased inflammation, drives the degradation of articular cartilage, which is a key characteristic of OA, the leading cause of pain and disability worldwide (13)(14)(15). It has been shown that many anabolic and catabolic pathways in articular cartilage have different daily dynamics, driven by a functional circadian clock in chondrocytes, that help maintain cartilage homeostasis (4,9,(16)(17)(18)(19)(20)(21)(22)(23). Several cellular functions exhibit time of day-dependent activity, including metabolic, ECM remodeling, and catabolic pathways (4,20), and disruptions in the clock cause loss in rhythmic expression and altered expression of these pathways (20).…”

Section: Introductionmentioning

confidence: 99%

Synthetic gene circuits for preventing disruption of the circadian clock due to interleukin-1–induced inflammation

et al. 2022

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The circadian clock regulates tissue homeostasis through temporal control of tissue-specific clock-controlled genes. In articular cartilage, disruptions in the circadian clock are linked to a procatabolic state. In the presence of inflammation, the cartilage circadian clock is disrupted, which further contributes to the pathogenesis of diseases such as osteoarthritis. Using synthetic biology and tissue engineering, we developed and tested genetically engineered cartilage from murine induced pluripotent stem cells (miPSCs) capable of preserving the circadian clock in the presence of inflammation. We found that circadian rhythms arise following chondrogenic differentiation of miPSCs. Exposure of tissue-engineered cartilage to the inflammatory cytokine interleukin-1 (IL-1) disrupted circadian rhythms and degraded the cartilage matrix. All three inflammation-resistant approaches showed protection against IL-1–induced degradation and loss of circadian rhythms. These synthetic gene circuits reveal a unique approach to support daily rhythms in cartilage and provide a strategy for creating cell-based therapies to preserve the circadian clock.

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A matter of time: Circadian clocks in osteoarthritis and the potential of chronotherapy

Cited by 13 publications

References 139 publications

Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration

Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration

Regulation and Role of Transcription Factors in Osteogenesis

Synthetic gene circuits for preventing disruption of the circadian clock due to interleukin-1–induced inflammation

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