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The role of the circadian clock in rheumatoid arthritis.

Gibbs JE, Ray DW - Arthritis Res. Ther. (2013)

Bottom Line: This temporal variation in disease pathology is directed by the circadian clock, both at a systemic level, through signalling pathways derived in the central clock, and at a local level by autonomous clocks found within inflammatory organs and cells.Employing the knowledge we have about how the inflammatory response is regulated by the clock will facilitate the development of chronotherapy regimens to improve the efficacy of current treatment strategies.Furthermore, a full understanding of the mechanisms by which the clock couples to the immune system may provide novel therapeutic targets for the treatment of this debilitating disease.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Rheumatoid arthritis exhibits diurnal variation in symptoms, with patients suffering with increased painful joint stiffness in the early morning. This correlates with an early morning rise in circulating levels of pro-inflammatory cytokines, such as interleukin-6. This temporal variation in disease pathology is directed by the circadian clock, both at a systemic level, through signalling pathways derived in the central clock, and at a local level by autonomous clocks found within inflammatory organs and cells. Indeed, many cellular components of the immune system, which are involved in the pathogenesis of rheumatoid arthritis, possess independent clocks that facilitate temporal gating of their functions. Furthermore, the circadian clock regulates the expression and activity of several genes and proteins that have demonstrated roles in progression of this autoimmune disease. These include a number of nuclear receptors and also fat-derived adipokines. Employing the knowledge we have about how the inflammatory response is regulated by the clock will facilitate the development of chronotherapy regimens to improve the efficacy of current treatment strategies. Furthermore, a full understanding of the mechanisms by which the clock couples to the immune system may provide novel therapeutic targets for the treatment of this debilitating disease.

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The molecular clock. CLOCK and BMAL heterodimers activate the transcription of per, cry, rev-erb and ror via E box elements on the promoters. The transcribed PER and CRY proteins form a multimeric complex, enter the nucleus and inhibit CLOCK/BMAL-mediated transcription. The PER/CRY complex is degraded during the night, thereby releasing this inhibitory effect and allowing a new cycle of transcription to begin. REV-ERB and ROR proteins compete for a response element (RORE) on the promoter of bmal, thereby repressing and activating transcription accordingly.
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Figure 2: The molecular clock. CLOCK and BMAL heterodimers activate the transcription of per, cry, rev-erb and ror via E box elements on the promoters. The transcribed PER and CRY proteins form a multimeric complex, enter the nucleus and inhibit CLOCK/BMAL-mediated transcription. The PER/CRY complex is degraded during the night, thereby releasing this inhibitory effect and allowing a new cycle of transcription to begin. REV-ERB and ROR proteins compete for a response element (RORE) on the promoter of bmal, thereby repressing and activating transcription accordingly.

Mentions: The molecular machinery required to enable a cell to oscillate comprises a transcription/translation feedback loop (Figure 2). Central to this loop are the genes clock and bmal, whose encoded proteins dimerise (CLOCK/BMAL) and bind to E-box elements on the promoters of the clock genes period (per), cryptochrome (cry), rev-erb and ror to activate their transcription. Translated PER and CRY form a dimeric complex (PER/CRY), enter the nucleus and inhibit CLOCK/BMAL transactivation. Subsequent degradation of PER/CRY allows CLOCK/BMAL to start a new cycle of transcriptional activation. A second feedback loop is formed by the action of ROR and REV-ERB proteins on bmal transcription; these nuclear receptors activate (ROR) and repress (REV-ERB) transcription through their competitive action on response elements (ROREs) on the bmal promoter. Initially thought of as an auxillary stabilising loop, it is now considered that this circuit is required for circadian oscillation [5]. In addition to these core clock genes, numerous other 'clock-controlled genes' show circadian patterns of expression as a result of action on E boxes, D box enhancers, and RORE sites.


The role of the circadian clock in rheumatoid arthritis.

Gibbs JE, Ray DW - Arthritis Res. Ther. (2013)

The molecular clock. CLOCK and BMAL heterodimers activate the transcription of per, cry, rev-erb and ror via E box elements on the promoters. The transcribed PER and CRY proteins form a multimeric complex, enter the nucleus and inhibit CLOCK/BMAL-mediated transcription. The PER/CRY complex is degraded during the night, thereby releasing this inhibitory effect and allowing a new cycle of transcription to begin. REV-ERB and ROR proteins compete for a response element (RORE) on the promoter of bmal, thereby repressing and activating transcription accordingly.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672712&req=5

Figure 2: The molecular clock. CLOCK and BMAL heterodimers activate the transcription of per, cry, rev-erb and ror via E box elements on the promoters. The transcribed PER and CRY proteins form a multimeric complex, enter the nucleus and inhibit CLOCK/BMAL-mediated transcription. The PER/CRY complex is degraded during the night, thereby releasing this inhibitory effect and allowing a new cycle of transcription to begin. REV-ERB and ROR proteins compete for a response element (RORE) on the promoter of bmal, thereby repressing and activating transcription accordingly.
Mentions: The molecular machinery required to enable a cell to oscillate comprises a transcription/translation feedback loop (Figure 2). Central to this loop are the genes clock and bmal, whose encoded proteins dimerise (CLOCK/BMAL) and bind to E-box elements on the promoters of the clock genes period (per), cryptochrome (cry), rev-erb and ror to activate their transcription. Translated PER and CRY form a dimeric complex (PER/CRY), enter the nucleus and inhibit CLOCK/BMAL transactivation. Subsequent degradation of PER/CRY allows CLOCK/BMAL to start a new cycle of transcriptional activation. A second feedback loop is formed by the action of ROR and REV-ERB proteins on bmal transcription; these nuclear receptors activate (ROR) and repress (REV-ERB) transcription through their competitive action on response elements (ROREs) on the bmal promoter. Initially thought of as an auxillary stabilising loop, it is now considered that this circuit is required for circadian oscillation [5]. In addition to these core clock genes, numerous other 'clock-controlled genes' show circadian patterns of expression as a result of action on E boxes, D box enhancers, and RORE sites.

Bottom Line: This temporal variation in disease pathology is directed by the circadian clock, both at a systemic level, through signalling pathways derived in the central clock, and at a local level by autonomous clocks found within inflammatory organs and cells.Employing the knowledge we have about how the inflammatory response is regulated by the clock will facilitate the development of chronotherapy regimens to improve the efficacy of current treatment strategies.Furthermore, a full understanding of the mechanisms by which the clock couples to the immune system may provide novel therapeutic targets for the treatment of this debilitating disease.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Rheumatoid arthritis exhibits diurnal variation in symptoms, with patients suffering with increased painful joint stiffness in the early morning. This correlates with an early morning rise in circulating levels of pro-inflammatory cytokines, such as interleukin-6. This temporal variation in disease pathology is directed by the circadian clock, both at a systemic level, through signalling pathways derived in the central clock, and at a local level by autonomous clocks found within inflammatory organs and cells. Indeed, many cellular components of the immune system, which are involved in the pathogenesis of rheumatoid arthritis, possess independent clocks that facilitate temporal gating of their functions. Furthermore, the circadian clock regulates the expression and activity of several genes and proteins that have demonstrated roles in progression of this autoimmune disease. These include a number of nuclear receptors and also fat-derived adipokines. Employing the knowledge we have about how the inflammatory response is regulated by the clock will facilitate the development of chronotherapy regimens to improve the efficacy of current treatment strategies. Furthermore, a full understanding of the mechanisms by which the clock couples to the immune system may provide novel therapeutic targets for the treatment of this debilitating disease.

Show MeSH
Related in: MedlinePlus