Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain

Vaskar Das, Ranjan Kc, Xin Li, Disha Varma, Sujun Qiu, Jeffrey S. Kroin, Christopher B. Forsyth, Ali Keshavarzian, Andre J van Wijnen, Thomas J. Park, Gary S. Stein, Insug O-Sullivan, Thomas P. Burris, Hee Jeong Im

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clearly demonstrate that genetic disruption of the molecular clock, via deletion of bmal1 in the sensory neurons of the DRG, decreases pain in a model of OA. Furthermore, pharmacological activation of REV-ERB leading to suppression of BMAL1 expression may be an effective method for treating OA-related pain, as well as to reduce joint damage associated with this disease.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalGene
Volume655
DOIs
StatePublished - May 20 2018

Fingerprint

Osteoarthritis
Analgesics
Pharmacology
Pain
Hyperalgesia
Diagnosis-Related Groups
Sensory Receptor Cells
Circadian Rhythm
Genes
Cartilage
Molecular Biology
Knee
Joints
Neurons
SR9009

Keywords

  • BMAL1
  • Circadian disruption
  • Clock gene
  • OA
  • Osteoarthritis
  • Pain
  • REV-ERB
  • SR9009

ASJC Scopus subject areas

  • Genetics

Cite this

Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain. / Das, Vaskar; Kc, Ranjan; Li, Xin; Varma, Disha; Qiu, Sujun; Kroin, Jeffrey S.; Forsyth, Christopher B.; Keshavarzian, Ali; van Wijnen, Andre J; Park, Thomas J.; Stein, Gary S.; O-Sullivan, Insug; Burris, Thomas P.; Im, Hee Jeong.

In: Gene, Vol. 655, 20.05.2018, p. 1-12.

Research output: Contribution to journalArticle

Das, V, Kc, R, Li, X, Varma, D, Qiu, S, Kroin, JS, Forsyth, CB, Keshavarzian, A, van Wijnen, AJ, Park, TJ, Stein, GS, O-Sullivan, I, Burris, TP & Im, HJ 2018, 'Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain', Gene, vol. 655, pp. 1-12. https://doi.org/10.1016/j.gene.2018.02.048
Das, Vaskar ; Kc, Ranjan ; Li, Xin ; Varma, Disha ; Qiu, Sujun ; Kroin, Jeffrey S. ; Forsyth, Christopher B. ; Keshavarzian, Ali ; van Wijnen, Andre J ; Park, Thomas J. ; Stein, Gary S. ; O-Sullivan, Insug ; Burris, Thomas P. ; Im, Hee Jeong. / Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain. In: Gene. 2018 ; Vol. 655. pp. 1-12.
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abstract = "Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clearly demonstrate that genetic disruption of the molecular clock, via deletion of bmal1 in the sensory neurons of the DRG, decreases pain in a model of OA. Furthermore, pharmacological activation of REV-ERB leading to suppression of BMAL1 expression may be an effective method for treating OA-related pain, as well as to reduce joint damage associated with this disease.",
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AU - Kroin, Jeffrey S.

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AU - Keshavarzian, Ali

AU - van Wijnen, Andre J

AU - Park, Thomas J.

AU - Stein, Gary S.

AU - O-Sullivan, Insug

AU - Burris, Thomas P.

AU - Im, Hee Jeong

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N2 - Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clearly demonstrate that genetic disruption of the molecular clock, via deletion of bmal1 in the sensory neurons of the DRG, decreases pain in a model of OA. Furthermore, pharmacological activation of REV-ERB leading to suppression of BMAL1 expression may be an effective method for treating OA-related pain, as well as to reduce joint damage associated with this disease.

AB - Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clearly demonstrate that genetic disruption of the molecular clock, via deletion of bmal1 in the sensory neurons of the DRG, decreases pain in a model of OA. Furthermore, pharmacological activation of REV-ERB leading to suppression of BMAL1 expression may be an effective method for treating OA-related pain, as well as to reduce joint damage associated with this disease.

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