The circadian clock: a central mediator of cartilage maintenance and osteoarthritis development?

Rheumatology ◽  
2021 ◽  
Author(s):  
Raewyn C Poulsen ◽  
James I Hearn ◽  
Nicola Dalbeth
Keyword(s):  
Circadian Clock ◽  
Current Knowledge ◽  
Cell Signalling ◽  
The Core ◽  
Tissue Degeneration ◽  
Cell Tissue ◽  
Clock Component ◽  
Oa Chondrocytes ◽  
Cell Signalling Pathway ◽  
Oxidative Insult

Abstract The circadian clock is a specialized cell signalling pathway present in all cells. Loss of clock function leads to tissue degeneration and premature ageing in animal models demonstrating the fundamental importance of clocks for cell, tissue and organism health. There is now considerable evidence that the chondrocyte circadian clock is altered in OA. The purpose of this review is to summarize current knowledge regarding the nature of the change in the chondrocyte clock in OA and the implications of this change for disease development. Expression of the core clock component, BMAL1, has consistently been shown to be lower in OA chondrocytes. This may contribute to changes in chondrocyte differentiation and extracellular matrix turnover in disease. Circadian clocks are highly responsive to environmental factors. Mechanical loading, diet, inflammation and oxidative insult can all influence clock function. These factors may contribute to causing the change in the chondrocyte clock in OA.

scholarly journals GIGANTEA gates gibberellin signaling through stabilization of the DELLA proteins in Arabidopsis

2019 ◽  
Vol 116 (43) ◽  
pp. 21893-21899 ◽  
Author(s):  
Maria A. Nohales ◽  
Steve A. Kay
Keyword(s):  
Circadian Clock ◽  
Signaling Pathways ◽  
Hormone Signaling ◽  
The Core ◽  
Della Proteins ◽  
Physiological Processes ◽  
Ga Signaling ◽  
Clock Component ◽  
Mechanistic Understanding ◽  
Gibberellin Signaling

Circadian clock circuitry intersects with a plethora of signaling pathways to adequately time physiological processes to occur at the most appropriate time of the day and year. However, our mechanistic understanding of how the clockwork is wired to its output is limited. Here we uncover mechanistic connections between the core clock component GIGANTEA (GI) and hormone signaling through the modulation of key components of the transduction pathways. Specifically, we show how GI modulates gibberellin (GA) signaling through the stabilization of the DELLA proteins, which act as negative components in the signaling of this hormone. GI function within the GA pathway is required to precisely time the permissive gating of GA sensitivity, thereby determining the phase of GA-regulated physiological outputs.

Altered expression of the core circadian clock component PERIOD2 contributes to osteoarthritis-like changes in chondrocyte activity

2018 ◽  
Vol 36 (3) ◽  
pp. 319-331 ◽  
Author(s):  
Jing Rong ◽  
Mark Zhu ◽  
Jacob Munro ◽  
Jillian Cornish ◽  
Geraldine M McCarthy ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Altered Expression ◽  
The Core ◽  
Clock Component

scholarly journals Molecular convergence of clock and photosensory pathways through PIF3–TOC1 interaction and co-occupancy of target promoters

2016 ◽  
Vol 113 (17) ◽  
pp. 4870-4875 ◽  
Author(s):  
Judit Soy ◽  
Pablo Leivar ◽  
Nahuel González-Schain ◽  
Guiomar Martín ◽  
Céline Diaz ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Circadian Clock ◽  
Transcriptional Activation ◽  
Protein Abundance ◽  
The Core ◽  
Collective Activity ◽  
Clock Component ◽  
Growth Promoting ◽  
Circadian Clock Output ◽  
Target Promoters

A mechanism for integrating light perception and the endogenous circadian clock is central to a plant’s capacity to coordinate its growth and development with the prevailing daily light/dark cycles. Under short-day (SD) photocycles, hypocotyl elongation is maximal at dawn, being promoted by the collective activity of a quartet of transcription factors, called PIF1, PIF3, PIF4, and PIF5 (phytochrome-interacting factors). PIF protein abundance in SDs oscillates as a balance between synthesis and photoactivated-phytochrome–imposed degradation, with maximum levels accumulating at the end of the long night. Previous evidence shows that elongation under diurnal conditions (as well as in shade) is also subjected to circadian gating. However, the mechanism underlying these phenomena is incompletely understood. Here we show that the PIFs and the core clock component Timing of CAB expression 1 (TOC1) display coincident cobinding to the promoters of predawn-phased, growth-related genes under SD conditions. TOC1 interacts with the PIFs and represses their transcriptional activation activity, antagonizing PIF-induced growth. Given the dynamics of TOC1 abundance (displaying high postdusk levels that progressively decline during the long night), our data suggest that TOC1 functions to provide a direct output from the core clock that transiently constrains the growth-promoting activity of the accumulating PIFs early postdusk, thereby gating growth to predawn, when conditions for cell elongation are optimal. These findings unveil a previously unrecognized mechanism whereby a core circadian clock output signal converges immediately with the phytochrome photosensory pathway to coregulate directly the activity of the PIF transcription factors positioned at the apex of a transcriptional network that regulates a diversity of downstream morphogenic responses.

scholarly journals Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽  
2021 ◽  
Vol 372 (6539) ◽  
pp. eabe9230 ◽  
Author(s):  
Elan Ness-Cohn ◽  
Ravi Allada ◽  
Rosemary Braun
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Insufficient Evidence ◽  
The Core ◽  
Clock Component ◽  
Mouse Tissues ◽  
Associated Data

Ray et al. (Reports, 14 February 2020, p. 800) report apparent transcriptional circadian rhythms in mouse tissues lacking the core clock component BMAL1. To better understand these surprising results, we reanalyzed the associated data. We were unable to reproduce the original findings, nor could we identify reliably cycling genes. We conclude that there is insufficient evidence to support circadian transcriptional rhythms in the absence of Bmal1.

scholarly journals Circadian clock protein Rev-erbα regulates neuroinflammation

2019 ◽  
Vol 116 (11) ◽  
pp. 5102-5107 ◽  
Author(s):  
Percy Griffin ◽  
Julie M. Dimitry ◽  
Patrick W. Sheehan ◽  
Brian V. Lananna ◽  
Chun Guo ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Microglial Activation ◽  
Time Of Day ◽  
Resting State Functional Connectivity ◽  
Promoter Regions ◽  
Clock Component ◽  
Glial Cultures ◽  
Inflammatory Phenotype

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα−/− mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα−/− mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα−/− microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα−/− mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα−/− mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

Cell signalling pathway involved in PACAP-induced AR4-2J cell proliferation

1995 ◽  
Vol 7 (3) ◽  
pp. 195-205 ◽  
Author(s):  
Jean Morisset ◽  
Nadine Douziech ◽  
Grazyna Rydzewska ◽  
Louis Buscail ◽  
Nathalie Rivard
Keyword(s):  
Cell Proliferation ◽  
Cell Signalling ◽  
Signalling Pathway ◽  
Cell Signalling Pathway

scholarly journals Machine Learning Helps Identify CHRONO as a Circadian Clock Component

PLoS Biology ◽  
2014 ◽  
Vol 12 (4) ◽  
pp. e1001840 ◽  
Author(s):  
Ron C. Anafi ◽  
Yool Lee ◽  
Trey K. Sato ◽  
Anand Venkataraman ◽  
Chidambaram Ramanathan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Circadian Clock ◽  
Clock Component

scholarly journals Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
Mija Marinković ◽  
Matilda Šprung ◽  
Maja Buljubašić ◽  
Ivana Novak
Keyword(s):  
Therapeutic Strategy ◽  
Current Knowledge ◽  
Therapeutic Agents ◽  
Therapeutic Strategies ◽  
Human Diseases ◽  
The Core ◽  
Future Drug ◽  
Autophagic Activity ◽  
Tumor Types ◽  
Catabolic Process

In the last two decades, accumulating evidence pointed to the importance of autophagy in various human diseases. As an essential evolutionary catabolic process of cytoplasmatic component digestion, it is generally believed that modulating autophagic activity, through targeting specific regulatory actors in the core autophagy machinery, may impact disease processes. Both autophagy upregulation and downregulation have been found in cancers, suggesting its dual oncogenic and tumor suppressor properties during malignant transformation. Identification of the key autophagy targets is essential for the development of new therapeutic agents. Despite this great potential, no therapies are currently available that specifically focus on autophagy modulation. Although drugs like rapamycin, chloroquine, hydroxychloroquine, and others act as autophagy modulators, they were not originally developed for this purpose. Thus, autophagy may represent a new and promising pharmacologic target for future drug development and therapeutic applications in human diseases. Here, we summarize our current knowledge in regard to the interplay between autophagy and malignancy in the most significant tumor types: pancreatic, breast, hepatocellular, colorectal, and lung cancer, which have been studied in respect to autophagy manipulation as a promising therapeutic strategy. Finally, we present an overview of the most recent advances in therapeutic strategies involving autophagy modulators in cancer.

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