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      Insights into the Role of Circadian Rhythms in Bone Metabolism: A Promising Intervention Target?

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          Numerous physiological processes of mammals, including bone metabolism, are regulated by the circadian clock system, which consists of a central regulator, the suprachiasmatic nucleus (SCN), and the peripheral oscillators of the BMAL1/CLOCK-PERs/CRYs system. Various bone turnover markers and bone metabolism-regulating hormones such as melatonin and parathyroid hormone (PTH) display diurnal rhythmicity. According to previous research, disruption of the circadian clock due to shift work, sleep restriction, or clock gene knockout is associated with osteoporosis or other abnormal bone metabolism, showing the importance of the circadian clock system for maintaining homeostasis of bone metabolism. Moreover, common causes of osteoporosis, including postmenopausal status and aging, are associated with changes in the circadian clock. In our previous research, we found that agonism of the circadian regulators REV-ERBs inhibits osteoclast differentiation and ameliorates ovariectomy-induced bone loss in mice, suggesting that clock genes may be promising intervention targets for abnormal bone metabolism. Moreover, osteoporosis interventions at different time points can provide varying degrees of bone protection, showing the importance of accounting for circadian rhythms for optimal curative effects in clinical treatment of osteoporosis. In this review, we summarize current knowledge about circadian rhythms and bone metabolism.

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          The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

          Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.
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            Molecular components of the mammalian circadian clock.

            Circadian rhythms are approximately 24-h oscillations in behavior and physiology, which are internally generated and function to anticipate the environmental changes associated with the solar day. A conserved transcriptional-translational autoregulatory loop generates molecular oscillations of 'clock genes' at the cellular level. In mammals, the circadian system is organized in a hierarchical manner, in which a master pacemaker in the suprachiasmatic nucleus (SCN) regulates downstream oscillators in peripheral tissues. Recent findings have revealed that the clock is cell-autonomous and self-sustained not only in a central pacemaker, the SCN, but also in peripheral tissues and in dissociated cultured cells. It is becoming evident that specific contribution of each clock component and interactions among the components vary in a tissue-specific manner. Here, we review the general mechanisms of the circadian clockwork, describe recent findings that elucidate tissue-specific expression patterns of the clock genes and address the importance of circadian regulation in peripheral tissues for an organism's overall well-being.
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              Resetting of circadian time in peripheral tissues by glucocorticoid signaling.

              In mammals, circadian oscillators reside not only in the suprachiasmatic nucleus of the brain, which harbors the central pacemaker, but also in most peripheral tissues. Here, we show that the glucocorticoid hormone analog dexamethasone induces circadian gene expression in cultured rat-1 fibroblasts and transiently changes the phase of circadian gene expression in liver, kidney, and heart. However, dexamethasone does not affect cyclic gene expression in neurons of the suprachiasmatic nucleus. This enabled us to establish an apparent phase-shift response curve specifically for peripheral clocks in intact animals. In contrast to the central clock, circadian oscillators in peripheral tissues appear to remain responsive to phase resetting throughout the day.

                Author and article information

                Biomed Res Int
                Biomed Res Int
                BioMed Research International
                27 September 2018
                : 2018
                1Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                2Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
                3Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                Author notes

                Academic Editor: Giuseppe Piccione

                Copyright © 2018 Chao Song et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: National Key Research and Development Program of China
                Award ID: 2016YFB1101305
                Funded by: National Natural Science Foundation of China
                Award ID: 81472133
                Review Article


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