Top

16-06-2016 | Osteoarthritis | Review | Article

The brain–joint axis in osteoarthritis: nerves, circadian clocks and beyond

Journal: Nature Reviews Rheumatology

Authors: Francis Berenbaum, Qing-Jun Meng

Publisher: Nature Publishing Group UK

Abstract

Osteoarthritis (OA) is a prevalent and debilitating joint disease for which ageing, obesity and chronic inflammation are known risk factors. The central, peripheral and autonomic nervous systems are essential in all metabolic systems, and emerging evidence suggests a role for these systems in OA. In the past few years, metabolic diseases, such as obesity or diabetes, have been linked to disruption of circadian rhythms that are tightly regulated by the nervous system, whereas inflammatory and autoimmune diseases are known to be linked to disruption of the cholinergic vagus nerve reflex. Interestingly, metabolism, inflammation and circadian rhythms have all been linked to the development and progression of OA. This article reviews current knowledge of the direct and indirect roles of the nervous system and circadian system in the initiation and/or progression of OA, and highlights the directions for future research in this emerging field.

Nat Rev Rheumatol 2016;12:508–516. doi:10.1038/nrrheum.2016.93

Hoy, D. G. et al. Reflecting on the global burden of musculoskeletal conditions: lessons learnt from the global burden of disease 2010 study and the next steps forward. Ann. Rheum. Dis. 74, 4–7 (2015).CrossRefPubMed

Vos, T. et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2163–2196 (2012).PubMedPubMedCentral

Goldring, M. B. & Berenbaum, F. Emerging targets in osteoarthritis therapy. Curr. Opin. Pharmacol. 22, 51–63 (2015).CrossRefPubMedPubMedCentral

Bijlsma, J. W., Berenbaum, F. & Lafeber, F. P. Osteoarthritis: an update with relevance for clinical practice. Lancet 377, 2115–2126 (2011).CrossRefPubMed

Heilbronn, L. K. & Campbell, L. V. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr. Pharm. Des. 14, 1225–1230 (2008).CrossRefPubMed

Duncan, B. B. et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 52, 1799–1805 (2003).CrossRefPubMed

Yusuf, E. et al. Association between weight or body mass index and hand osteoarthritis: a systematic review. Ann. Rheum. Dis. 69, 761–765 (2010).CrossRefPubMed

Courties, A., Gualillo, O., Berenbaum, F. & Sellam, J. Metabolic stress-induced joint inflammation and osteoarthritis. Osteoarthritis Cartilage 23, 1955–1965 (2015).CrossRefPubMed

Huang, Z. & Kraus, V. B. Does lipopolysaccharide-mediated inflammation have a role in OA? Nat. Rev. Rheumatol. 12, 123–129 (2016).CrossRefPubMed

10.

Sohn, D. H. et al. Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4. Arthritis Res. Ther. 14, R7 (2012).CrossRefPubMedPubMedCentral

11.

Kyrkanides, S. et al. Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice. J. Neuroinflamm. 8, 112 (2011).CrossRef

12.

Verzijl, N. et al. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum. 46, 114–123 (2002).CrossRefPubMed

13.

Loeser, R. F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 17, 971–979 (2009).CrossRefPubMedPubMedCentral

14.

Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).CrossRefPubMed

15.

Tracey, K. J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117, 289–296 (2007).CrossRefPubMedPubMedCentral

16.

Cermakian, N. & Sassone-Corsi, P. Multilevel regulation of the circadian clock. Nat. Rev. Mol. Cell Biol. 1, 59–67 (2000).CrossRefPubMed

17.

Gamble, K. L., Berry, R., Frank, S. J. & Young, M. E. Circadian clock control of endocrine factors. Nat. Rev. Endocrinol. 10, 466–475 (2014).CrossRefPubMedPubMedCentral

18.

Roenneberg, T. & Merrow, M. Circadian clocks — the fall and rise of physiology. Nat. Rev. Mol. Cell Biol. 6, 965–971 (2005).CrossRefPubMed

19.

Takahashi, J. S., Hong, H.-K., Ko, C. H. & McDearmon, E. L. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat. Rev. Genet. 9, 764–775 (2008).CrossRefPubMedPubMedCentral

20.

Yoo, S. H. et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl Acad. Sci. USA 101, 5339–5346 (2004).CrossRefPubMedPubMedCentral

21.

Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).CrossRefPubMed

22.

Pezuk, P., Mohawk, J. A., Wang, L. A. & Menaker, M. Glucocorticoids as entraining signals for peripheral circadian oscillators. Endocrinology 153, 4775–4783 (2012).CrossRefPubMedPubMedCentral

23.

Reddy, A. B. et al. Glucocorticoid signaling synchronizes the liver circadian transcriptome. Hepatology 45, 1478–1488 (2007).CrossRefPubMed

24.

Herzog, E. D. & Muglia, L. J. You are when you eat. Nat. Neurosci. 9, 300–302 (2006).CrossRefPubMed

25.

Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).CrossRefPubMedPubMedCentral

26.

Sladek, M. et al. Insight into the circadian clock within rat colonic epithelial cells. Gastroenterology 133, 1240–1249 (2007).CrossRefPubMed

27.

Le Minh, N., Damiola, F., Tronche, F., Schutz, G. & Schibler, U. Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators. EMBO J. 20, 7128–7136 (2001).CrossRefPubMedPubMedCentral

28.

Buhr, E. D., Yoo, S. H. & Takahashi, J. S. Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330, 379–385 (2010).CrossRefPubMedPubMedCentral

29.

Hut, R. A. & Van der Zee, E. A. The cholinergic system, circadian rhythmicity, and time memory. Behav. Brain Res. 221, 466–480 (2011).CrossRefPubMed

30.

Gillette, M. U. et al. Role of the M1 receptor in regulating circadian rhythms. Life Sci. 68, 2467–2472 (2001).CrossRefPubMed

31.

Liu, C. & Gillette, M. U. Cholinergic regulation of the suprachiasmatic nucleus circadian rhythm via a muscarinic mechanism at night. J. Neurosci. 16, 744–751 (1996).CrossRefPubMedPubMedCentral

32.

Kalsbeek, A. et al. Circadian rhythms in the hypothalamo–pituitary–adrenal (HPA) axis. Mol. Cell. Endocrinol. 349, 20–29 (2012).CrossRefPubMed

33.

Nader, N., Chrousos, G. P. & Kino, T. Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol. Metab. 21, 277–286 (2010).CrossRefPubMedPubMedCentral

34.

Spies, C. M., Straub, R. H., Cutolo, M. & Buttgereit, F. Circadian rhythms in rheumatology — a glucocorticoid perspective. Arthritis Res. Ther. 16, S3 (2014).CrossRefPubMedPubMedCentral

35.

Straub, R. H., Bijlsma, J. W., Masi, A. & Cutolo, M. Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases — the 10-year update. Semin. Arthritis Rheum. 43, 392–404 (2013).CrossRefPubMed

36.

Meulenbelt, I. et al. Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis. Hum. Mol. Genet. 17, 1867–1875 (2008).CrossRefPubMed

37.

Hinoi, E. et al. Up-regulation of per mRNA expression by parathyroid hormone through a protein kinase A-CREB-dependent mechanism in chondrocytes. J. Biol. Chem. 281, 23632–23642 (2006).CrossRefPubMed

38.

Jänig, W. Sympathetic nervous system and inflammation: a conceptual view. Auton. Neurosci. 182, 4–14 (2014).CrossRefPubMed

39.

Abboud, F. M. In search of autonomic balance: the good, the bad, and the ugly. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1449–R1467 (2010).CrossRefPubMedPubMedCentral

40.

Rosas-Ballina, M. & Tracey, K. J. Cholinergic control of inflammation. J. Intern. Med. 265, 663–679 (2009).CrossRefPubMedPubMedCentral

41.

Liu, Y. et al. Activation of α7 nicotinic acetylcholine receptors prevents monosodium iodoacetate-induced osteoarthritis in rats. Cell. Physiol. Biochem. 35, 627–638 (2015).CrossRefPubMed

42.

Takarada, T. et al. Interference by adrenaline with chondrogenic differentiation through suppression of gene transactivation mediated by Sox9 family members. Bone 45, 568–578 (2009).CrossRefPubMed

43.

Jenei-Lanzl, Z. et al. Norepinephrine inhibition of mesenchymal stem cell and chondrogenic progenitor cell chondrogenesis and acceleration of chondrogenic hypertrophy. Arthritis Rheumatol. 66, 2472–2481 (2014).CrossRefPubMed

44.

Lai, L. P. & Mitchell, J. β2-adrenergic receptors expressed on murine chondrocytes stimulate cellular growth and inhibit the expression of Indian hedgehog and collagen type X. J. Cell. Biochem. 104, 545–553 (2008).CrossRefPubMed

45.

Mitchell, J., Lai, L. P., Peralta, F., Xu, Y. & Sugamori, K. β2-adrenergic receptors inhibit the expression of collagen type II in growth plate chondrocytes by stimulating the AP-1 factor Jun-B. Am. J. Physiol. Endocrinol. Metab. 300, E633–E639 (2011).CrossRefPubMed

46.

Vignon, E., Broquet, P., Mathieu, P., Louisot, P. & Richard, M. Histaminergic H1, serotoninergic, beta adrenergic and dopaminergic receptors in human osteoarthritic cartilage. Biochem. Int. 20, 251–255 (1990).PubMed

47.

Opolka, A., Straub, R. H., Pasoldt, A., Grifka, J. & Grassel, S. Substance P and norepinephrine modulate murine chondrocyte proliferation and apoptosis. Arthritis Rheum. 64, 729–739 (2012).CrossRefPubMed

48.

Fonseca, T. L. et al. Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype. J. Bone Miner. Res. 26, 591–603 (2011).CrossRefPubMed

49.

Mauro, L. J., Wenzel, S. J. & Sindberg, G. M. Regulation of chick bone growth by leptin and catecholamines. Poult. Sci. 89, 697–708 (2010).CrossRefPubMed

50.

Gossan, N. et al. The circadian clock in murine chondrocytes regulates genes controlling key aspects of cartilage homeostasis. Arthritis Rheum. 65, 2334–2345 (2013).CrossRefPubMedPubMedCentral

51.

Honda, K. K. et al. Different circadian expression of major matrix-related genes in various types of cartilage: modulation by light-dark conditions. J. Biochem. 154, 373–381 (2013).CrossRefPubMed

52.

Andersson, M. L. et al. Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis. Ann. Rheum. Dis. 65, 1490–1494 (2006).CrossRefPubMedPubMedCentral

53.

Kong, S. Y. et al. Diurnal variation of serum and urine biomarkers in patients with radiographic knee osteoarthritis. Arthritis Rheum. 54, 2496–2504 (2006).CrossRefPubMed

54.

Jubiz, W., Canterbury, J. M., Reiss, E. & Tyler, F. H. Circadian rhythm in serum parathyroid hormone concentration in human subjects: correlation with serum calcium, phosphate, albumin, and growth hormone levels. J. Clin. Invest. 51, 2040–2046 (1972).CrossRefPubMedPubMedCentral

55.

Okubo, N. et al. Parathyroid hormone resets the cartilage circadian clock of the organ-cultured murine femur. Acta Orthop. 86, 627–631 (2015).CrossRefPubMedPubMedCentral

56.

Kanbe, K., Inoue, K., Xiang, C. & Chen, Q. Identification of clock as a mechanosensitive gene by large-scale DNA microarray analysis: downregulation in osteoarthritic cartilage. Mod. Rheumatol. 16, 131–136 (2006).CrossRefPubMed

57.

Bass, J. Circadian topology of metabolism. Nature 491, 348–356 (2012).CrossRefPubMed

58.

Guo, B. et al. Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFsmall ka, CyrillicB-dependent pathway. Osteoarthritis Cartilage 23, 1981–1988 (2015).CrossRefPubMedPubMedCentral

59.

Dudek, M. et al. The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity. J. Clin. Invest. 126, 365–376 (2016).CrossRefPubMed

60.

Dudek, M. & Meng, Q. J. Running on time: the role of circadian clocks in the musculoskeletal system. Biochem. J. 463, 1–8 (2014).CrossRefPubMed

61.

Gundberg, C. M., Markowitz, M. E., Mizruchi, M. & Rosen, J. F. Osteocalcin in human serum: a circadian rhythm. J. Clin. Endocrinol. Metab. 60, 736–739 (1985).CrossRefPubMed

62.

Hassager, C., Risteli, J., Risteli, L., Jensen, S. B. & Christiansen, C. Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women. J. Bone Miner. Res. 7, 1307–1311 (1992).CrossRefPubMed

63.

Grundberg, E. et al. Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells. Physiol. Genomics 33, 301–311 (2008).CrossRefPubMed

64.

Maronde, E. et al. The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation. PLoS ONE 5, e11527 (2010).CrossRefPubMedPubMedCentral

65.

Fu, L., Patel, M. S., Bradley, A., Wagner, E. F. & Karsenty, G. The molecular clock mediates leptin-regulated bone formation. Cell 122, 803–815 (2005).CrossRefPubMed

66.

Samsa, W. E., Vasanji, A., Midura, R. J. & Kondratov, R. V. Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype. Bone 84, 194–203 (2016).CrossRefPubMedPubMedCentral

67.

Komoto, S., Kondo, H., Fukuta, O. & Togari, A. Comparison of β-adrenergic and glucocorticoid signaling on clock gene and osteoblast-related gene expressions in human osteoblast. Chronobiol. Int. 29, 66–74 (2012).CrossRefPubMed

68.

Fujihara, Y., Kondo, H., Noguchi, T. & Togari, A. Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes. Bone 61, 1–9 (2014).CrossRefPubMed

69.

Yeung, C. Y. et al. Gremlin-2 is a BMP antagonist that is regulated by the circadian clock. Sci. Rep. 4, 5183 (2014).CrossRefPubMedPubMedCentral

70.

McDearmon, E. L. et al. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science 314, 1304–1308 (2006).CrossRefPubMedPubMedCentral

71.

Bunger, M. K. et al. Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis 41, 122–132 (2005).CrossRefPubMed

72.

Brown, S. A., Pagani, L., Cajochen, C. & Eckert, A. Systemic and cellular reflections on ageing and the circadian oscillator: a mini-review. Gerontology 57, 427–434 (2011).PubMed

73.

Khapre, R. V., Kondratova, A. A., Susova, O. & Kondratov, R. V. Circadian clock protein BMAL1 regulates cellular senescence in vivo. Cell Cycle 10, 4162–4169 (2011).CrossRefPubMedPubMedCentral

74.

Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).CrossRefPubMedPubMedCentral

75.

Brown, S. A., Schmitt, K. & Eckert, A. Aging and circadian disruption: causes and effects. Aging 3, 813–817 (2011).CrossRefPubMedPubMedCentral

76.

Davidson, A. J., Yamazaki, S., Arble, D. M., Menaker, M. & Block, G. D. Resetting of central and peripheral circadian oscillators in aged rats. Neurobiol. Aging 29, 471–477 (2008).CrossRefPubMed

77.

Sellix, M. T. et al. Aging differentially affects the re-entrainment response of central and peripheral circadian oscillators. J. Neurosci. 32, 16193–16202 (2012).CrossRefPubMedPubMedCentral

78.

Pagani, L. et al. Serum factors in older individuals change cellular clock properties. Proc. Natl Acad. Sci. USA 108, 7218–7223 (2011).CrossRefPubMedPubMedCentral

79.

Shane Anderson, A. & Loeser, R. F. Why is osteoarthritis an age-related disease? Best Pract. Res. Clin. Rheumatol. 24, 15–26 (2010).CrossRefPubMedPubMedCentral

80.

Green, C. B., Takahashi, J. S. & Bass, J. The meter of metabolism. Cell 134, 728–742 (2008).CrossRefPubMedPubMedCentral

81.

Shi, S. Q., Ansari, T. S., McGuinness, O. P., Wasserman, D. H. & Johnson, C. H. Circadian disruption leads to insulin resistance and obesity. Curr. Biol. 23, 372–381 (2013).CrossRefPubMedPubMedCentral

82.

Zhuo, Q., Yang, W., Chen, J. & Wang, Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol. 8, 729–737 (2012).CrossRefPubMed

83.

Janich, P. et al. Human epidermal stem cell function is regulated by circadian oscillations. Cell Stem Cell 13, 745–753 (2013).CrossRefPubMed

84.

Bhosale, A. M. & Richardson, J. B. Articular cartilage: structure, injuries and review of management. Br. Med. Bull. 87, 77–95 (2008).CrossRefPubMed

85.

Kc, R. et al. Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint. J. Cell. Physiol. 230, 2174–2183 (2015).CrossRefPubMedPubMedCentral

86.

Matsushita, T. et al. The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin-1β in human chondrocytes. J. Orthop. Res. 31, 531–537 (2013).CrossRefPubMed

87.

Matsuzaki, T. et al. Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice. Ann. Rheum. Dis. 73, 1397–1404 (2014).CrossRefPubMed

88.

Gabay, O. et al. Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice. Ann. Rheum. Dis. 71, 613–616 (2012).CrossRefPubMed

89.

Gabay, O. et al. Sirtuin 1 enzymatic activity is required for cartilage homeostasis in vivo in a mouse model. Arthritis Rheum. 65, 159–166 (2013).CrossRefPubMedPubMedCentral

90.

Chang, H.-C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013).CrossRefPubMedPubMedCentral

91.

Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD⁺ biosynthesis. Science 324, 651–654 (2009).CrossRefPubMedPubMedCentral

92.

Nakahata, Y. et al. The NAD⁺-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008).CrossRefPubMedPubMedCentral

93.

Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD⁺ salvage pathway by CLOCK-SIRT1. Science 324, 654–657 (2009).CrossRefPubMedPubMedCentral

94.

Asher, G. et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317–328 (2008).PubMed

95.

Eckel-Mahan, K. & Sassone-Corsi, P. Metabolism control by the circadian clock and vice versa. Nat. Struct. Mol. Biol. 16, 462–467 (2009).CrossRefPubMedPubMedCentral

96.

la Fleur, S. E. & Serlie, M. J. The interaction between nutrition and the brain and its consequences for body weight gain and metabolism; studies in rodents and men. Best Pract. Res. Clin. Endocrinol. Metab. 28, 649–659 (2014).CrossRefPubMed

97.

Ruiter, M. et al. The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior. Diabetes 52, 1709–1715 (2003).CrossRefPubMed

98.

Ando, H. et al. Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology 146, 5631–5636 (2005).CrossRefPubMed

99.

Bodosi, B. et al. Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R1071–R1079 (2004).CrossRefPubMed

100.

Accili, D. et al. The mind and the belly: a glance at how the nervous system directs metabolism. Diabetes Obes. Metab. 16, 1–3 (2014).CrossRefPubMed

101.

Bellet, M. M. & Sassone-Corsi, P. Mammalian circadian clock and metabolism — the epigenetic link. J. Cell Sci. 123, 3837–3848 (2010).CrossRefPubMedPubMedCentral

102.

Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 6, 414–421 (2007).CrossRefPubMed

103.

Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Eng. J. Med. 363, 1521–1531 (2010).CrossRef

104.

European Medicines Agency. clinicaltrialsregister.eu, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-004805-34 (2014).

105.

European Medicines Agency. clinicaltrialsregister.eu, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-001136-37 (2015).

106.

Levine, Y. A. et al. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS ONE 9, e104530 (2014).CrossRefPubMedPubMedCentral

107.

Zitnik, R. J. Treatment of chronic inflammatory diseases with implantable medical devices. Ann. Rheum. Dis. 70, i67–i70 (2011).CrossRefPubMed

108.

Simoni, A. et al. A mechanosensory pathway to the Drosophila circadian clock. Science 343, 525–528 (2014).CrossRefPubMed

109.

Feillet, C. A. et al. Lack of food anticipation in Per2 mutant mice. Curr. Biol. 16, 2016–2022 (2006).CrossRefPubMed

110.

Hughes, A. T. & Piggins, H. D. Feedback actions of locomotor activity to the circadian clock. Prog. Brain Res. 199, 305–336 (2012).CrossRefPubMed

111.

Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014).CrossRefPubMedPubMedCentral

112.

Hirota, T. et al. Identification of small molecule activators of cryptochrome. Science 337, 1094–1097 (2012).CrossRefPubMedPubMedCentral

113.

Solt, L. A. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012).CrossRefPubMedPubMedCentral

114.

Meng, Q. J. et al. Ligand modulation of REV-ERBα function resets the peripheral circadian clock in a phasic manner. J. Cell Sci. 121, 3629–3635 (2008).CrossRefPubMed

115.

Meng, Q. J. et al. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc. Natl Acad. Sci. USA 107, 15240–15245 (2010).CrossRefPubMedPubMedCentral

116.

Kaur, G., Phillips, C., Wong, K. & Saini, B. Timing is important in medication administration: a timely review of chronotherapy research. Int. J. Clin. Pharm. 35, 344–358 (2013).CrossRefPubMed

117.

Levi, F., Le Louarn, C. & Reinberg, A. Timing optimizes sustained-release indomethacin treatment of osteoarthritis. Clin. Pharmacol. Ther. 37, 77–84 (1985).CrossRefPubMed

118.

Gautron, L., Elmquist, J. K. & Williams, K. W. Neural control of energy balance: translating circuits to therapies. Cell 161, 133–145 (2015).CrossRefPubMedPubMedCentral

Medicine Matters Rheumatology

Abstract