Similar articles

Abstract: Mammalian bone is constantly metabolized from the embryonic stage, and the maintenance of bone health depends on the dynamic balance between bone resorption and bone formation, mediated by osteoclasts and osteoblasts. It is widely recognized that circadian clock genes can regulate bone metabolism. In recent years, the regulation of bone metabolism by non-coding RNAs has become a hotspot of research. microRNAs can participate in bone catabolism and anabolism by targeting key factors related to bone metabolism, including circadian clock genes. However, research in this field has been conducted only in recent years and the mechanisms involved are not yet well established. Recent studies have focused on how to target circadian clock genes to treat some diseases, such as autoimmune diseases, but few have focused on the co-regulation of circadian clock genes and microRNAs in bone metabolic diseases. Therefore, in this paper we review the progress of research on the co-regulation of bone metabolism by circadian clock genes and microRNAs, aiming to provide new ideas for the prevention and treatment of bone metabolic diseases such as osteoporosis.

生物钟基因与microRNAs共同调控骨代谢的研究进展

李婷婷^1,2，张士花³，杨雨轩²，张玲莉²，元宇¹，邹军^2
1广州体育学院运动与健康学院，中国广州市，510500
²上海体育学院运动科学学院，中国上海市，200438
³山东体育学院研究生教育学院，中国济南市，250102
概要：哺乳动物的骨骼从胚胎阶段开始就不断地进行新陈代谢，骨骼健康状态的维持依赖于破骨细胞和成骨细胞介导的骨吸收和骨形成之间的动态平衡。人们普遍认为，生物钟基因可以调节骨代谢。近年来，非编码RNAs对骨代谢的调控已成为研究热点。MicroRNAs可以通过靶向与骨代谢相关的关键因素参与骨的分解代谢和合成代谢，其中包括生物钟基因。然而，这一领域的研究在最近几年才开始进行，所涉及的机制尚未明晰。最近的研究集中在如何靶向生物钟基因来治疗一些疾病（如自身免疫性疾病），但少有人关注生物钟基因和microRNAs在骨代谢疾病中的共同调控问题。因此，本文对生物钟基因和microRNAs共同调控骨代谢的研究进展进行了回顾，旨在为预防和治疗骨代谢疾病（如骨质疏松症）提供新的思路。

关键词：昼夜节律；生物钟基因；MicroRNAs；骨代谢

[1]AbeT, SatoT, YodaT, et al., 2019. The period circadian clock 2 gene responds to glucocorticoids and regulates osteogenic capacity. Regen Ther, 11:199-206.

[2]AlexanderRK, LiouYH, KnudsenNH, et al., 2020. Bmal1 integrates mitochondrial metabolism and macrophage activation. eLife, 9:e54090.

[3]AnK, ZhaoH, MiaoY, et al., 2020. A circadian rhythm-gated subcortical pathway for nighttime-light-induced depressive-like behaviors in mice. Nat Neurosci, 23(7):869-880.

[4]AnduagaAM, EvantalN, PatopIL, et al., 2019. Thermosensitive alternative splicing senses and mediates temperature adaptation in Drosophila. eLife, 8:e44642.

[5]ArvidsonNG, GudbjörnssonB, LarssonA, et al., 1997. The timing of glucocorticoid administration in rheumatoid arthritis. Ann Rheum Dis, 56(1):27-31.

[6]AryalRP, KwakPB, TamayoAG, et al., 2017. Macromolecular assemblies of the mammalian circadian clock. Mol Cell, 67(5):770-782.e6.

[7]BangJ, ChangHW, JungHR, et al., 2012. Melatonin attenuates clock gene Cryptochrome1, which may aggravates mouse anti-type II collagen antibody-induced arthritis. Rheumatol Int, 32(2):379-385.

[8]BartelDP, 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116(2):281-297.

[9]BartelDP, 2018. Metazoan microRNAs. Cell, 173(1):20-51.

[10]BekerMC, CaglayanB, CaglayanAB, et al., 2019. Interaction of melatonin and Bmal1 in the regulation of PI3K/AKT pathway components and cellular survival. Sci Rep, 9:19082.

[11]BekkiH, DuffyT, OkuboN, et al., 2020. Suppression of circadian clock protein cryptochrome 2 promotes osteoarthritis. Osteoarthritis Cartilage, 28(7):966-976.

[12]BenderdourM, FahmiH, BeaudetF, et al., 2011. Nuclear receptor retinoid-related orphan receptor α1 modulates the metabolic activity of human osteoblasts. J Cell Biochem, 112(8):2160-2169.

[13]BiancoJN, BergoglioV, LinYL, et al., 2019. Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner. Nat Commun, 10:910.

[14]BoothSL, CentiA, SmithSR, et al., 2013. The role of osteocalcin in human glucose metabolism: marker or mediator? Nat Rev Endocrinol, 9(1):43-55.

[15]BoucherH, VanneauxV, DometT, et al., 2016. Circadian clock genes modulate human bone marrow mesenchymal stem cell differentiation, migration and cell cycle. PLoS ONE, 11(1):e0146674.

[16]BungerMK, WalisserJA, SullivanR, et al., 2005. Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis, 41(3):122-132.

[17]ButtgereitF, MehtaD, KirwanJ, et al., 2013. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis, 72(2):204-210.

[18]CaiXY, ZhangP, WangS, et al., 2020. LncRNA FGD5 antisense RNA 1 upregulates RORA to suppress hypoxic injury of human cardiomyocyte cells by inhibiting oxidative stress and apoptosis via miR-195. Mol Med Rep, 22(6):4579-4588.

[19]CaoQ, ZhaoX, BaiJW, et al., 2017. Circadian clock cryptochrome proteins regulate autoimmunity. Proc Natl Acad Sci USA, 114(47):12548-12553.

[20]ChaiC, CoxB, YaishD, et al., 2020. Agonist of RORA attenuates nonalcoholic fatty liver progression in mice via up-regulation of microRNA 122. Gastroenterology, 159(3):999-1014.e9.

[21]ChanWCW, TanZJ, ToMKT, et al., 2021. Regulation and role of transcription factors in osteogenesis. Int J Mol Sci, 22(11):5445.

[22]ChappuisS, RippergerJA, SchnellA, et al., 2013. Role of the circadian clock gene Per2 in adaptation to cold temperature. Mol Metab, 2(3):184-193.

[23]ChenGJ, TangQM, YuSL, et al., 2020. The biological function of BMAL1 in skeleton development and disorders. Life Sci, 253:117636.

[24]ChenX, RosbashM, 2016. mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression. Proc Natl Acad Sci USA, 113(21):E2965-E2972.

[25]ChengHYM, PappJW, VarlamovaO, et al., 2007. MicroRNA modulation of circadian-clock period and entrainment. Neuron, 54(5):813-829.

[26]ColbertJF, FordJA, HaegerSM, et al., 2017. A model-specific role of microRNA-223 as a mediator of kidney injury during experimental sepsis. Am J Physiol Renal Physiol, 313(2):F553-F559.

[27]CurtisAM, FagundesCT, YangGR, et al., 2015. Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. Proc Natl Acad Sci USA, 112(23):7231-7236.

[28]DeBruyneJP, WeaverDR, ReppertSM, 2007. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci, 10(5):543-545.

[29]DevannaP, VernesSC, 2014. A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137. Sci Rep, 4:3994.

[30]DurringtonHJ, KrakowiakK, MeijerP, et al., 2020. Circadian asthma airway responses are gated by REV-ERBα. Eur Respir J, 56(6):1902407.

[31]FeeneyKA, HansenLL, PutkerM, et al., 2016. Daily magnesium fluxes regulate cellular timekeeping and energy balance. Nature, 532(7599):375-379.

[32]FerrariD, BianchiN, EltzschigHK, et al., 2016. MicroRNAs modulate the purinergic signaling network. Trends Mol Med, 22(10):905-918.

[33]FeskanichD, HankinsonSE, SchernhammerES, 2009. Nightshift work and fracture risk: the nurses’ health study. Osteoporos Int, 20(4):537-542.

[34]FogleKJ, ParsonKG, DahmNA, et al., 2011. CRYPTOCHROME is a blue-light sensor that regulates neuronal firing rate. Science, 331(6023):1409-1413.

[35]FuL, PatelMS, BradleyA, et al., 2005. The molecular clock mediates leptin-regulated bone formation. Cell, 122(5):803-815.

[36]FuSQ, KuwaharaM, UchidaY, et al., 2019. Circadian production of melatonin in cartilage modifies rhythmic gene expression. J Endocrinol, 241(2):161-173.

[37]FujiharaY, KondoH, NoguchiT, et al., 2014. Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes. Bone, 61:1-9.

[38]GaertnerVD, MichelS, CurtinJA, et al., 2019. Nocturnal asthma is affected by genetic interactions between RORA and NPSR1. Pediatr Pulmonol, 54(6):847-857.

[39]GaoQ, ZhouL, YangSY, et al., 2016. A novel role of microRNA 17-5p in the modulation of circadian rhythm. Sci Rep, 6:30070.

[40]GatfieldD, le MartelotG, VejnarCE, et al., 2009. Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev, 23(11):1313-1326.

[41]GonçalvesCF, MengQJ, 2019. Timing metabolism in cartilage and bone: links between circadian clocks and tissue homeostasis. J Endocrinol, 243(3):R29-R46.

[42]GuissartC, LatypovaX, RollierP, et al., 2018. Dual molecular effects of dominant RORA mutations cause two variants of syndromic intellectual disability with either autism or cerebellar ataxia. Am J Hum Genet, 102(5):744-759.

[43]GunturAR, KawaiM, LeP, et al., 2011. An essential role for the circadian-regulated gene nocturnin in osteogenesis: the importance of local timekeeping in skeletal homeostasis. Ann N Y Acad Sci, 1237(1):58-63.

[44]GuoJH, ChengP, YuanHY, et al., 2009. The exosome regulates circadian gene expression in a posttranscriptional negative feedback loop. Cell, 138(6):1236-1246.

[45]GuoXF, QiuW, LiuQL, et al., 2018. Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten pathways. Oncogene, 37(31):4239-4259.

[46]HeY, LinFW, ChenYQ, et al., 2015. Overexpression of the circadian clock gene Rev-erbα affects murine bone mesenchymal stem cell proliferation and osteogenesis. Stem Cells Dev, 24(10):1194-1204.

[47]HiraiT, 2018. Regulation of clock genes by adrenergic receptor signaling in osteoblasts. Neurochem Res, 43(1):129-135.

[48]HruskaKA, LanskeB, MoeOW, 2017. Crosstalk between kidney and bone—bench to bedside. Bone, 100:1-3.

[49]HuH, HeXD, ZhangYZ, et al., 2020. MicroRNA alterations for diagnosis, prognosis, and treatment of osteoporosis: a comprehensive review and computational functional survey. Front Genet, 11:181.

[50]HuangJL, FuYP, GanW, et al., 2020. Hepatic stellate cells promote the progression of hepatocellular carcinoma through microRNA-1246-RORα‍-Wnt/β‍-Catenin axis. Cancer Lett, 476:140-151.

[51]HuangZF, WeiH, WangX, et al., 2020. Icariin promotes osteogenic differentiation of BMSCs by upregulating BMAL1 expression via BMP signaling. Mol Med Rep, 21(3):1590-1596.

[52]JiangWL, ZhaoSL, JiangXH, et al., 2016. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett, 371(2):314-325.

[53]JiangWL, ZhaoSL, ShenJ, et al., 2018. The miR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance. Cell Death Dis, 9:149.

[54]JiangY, ZhouJP, ZhaoJS, et al., 2020. MiR-18a-downregulated RORA inhibits the proliferation and tumorigenesis of glioma using the TNF‍-‍α‍-‍mediated NF‍-‍‍κB signaling pathway. eBioMedicine,52:102651.

[55]JuC, WangM, TakE, et al., 2021. Hypoxia-inducible factor-1α‍-dependent induction of miR122 enhances hepatic ischemia tolerance. J Clin Invest, 131(7):e140300.

[56]KasinskiAL, KelnarK, StahlhutC, et al., 2015. A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer. Oncogene, 34(27):3547-3555.

[57]KatoY, KawamotoT, FujimotoK, et al., 2014. DEC1/STRA13/SHARP2 and DEC2/SHARP1 coordinate physiological processes, including circadian rhythms in response to environmental stimuli. Curr Top Dev Biol, 110:339-372.

[58]KhoslaS, 2013. Pathogenesis of age-related bone loss in humans. J Gerontol A Biol Sci Med Sci, 68(10):1226-1235.

[59]KimB, GuareguaV, ChenXB, et al., 2021. Characterization of a murine model system to study microRNA-147 during inflammatory organ injury. Inflammation, 44(4):‍1426-1440.

[60]KimK, KimJH, KimI, et al., 2020. Rev-erbα negatively regulates osteoclast and osteoblast differentiation through p38 MAPK signaling pathway. Mol Cells, 43(1):34-47.

[61]KobayashiM, MorinibuA, KoyasuS, et al., 2017. A circadian clock gene, PER2, activates HIF-1 as an effector molecule for recruitment of HIF-1α to promoter regions of its downstream genes. FEBS J, 284(22):3804-3816.

[62]KojimaS, GatfieldD, EsauCC, et al., 2010. MicroRNA-122 modulates the rhythmic expression profile of the circadian deadenylase Nocturnin in mouse liver. PLoS ONE, 5(6):e11264.

[63]KurienP, HsuPK, LeonJ, et al., 2019. Timeless mutation alters phase responsiveness and causes advanced sleep phase. Proc Natl Acad Sci USA, 116(24):12045-12053.

[64]KushibikiT, AwazuK, 2009. Blue laser irradiation enhances extracellular calcification of primary mesenchymal stem cells. Photomed Laser Surg, 27(3):493-498.

[65]LeeTJ, YuanXY, KerrK, et al., 2020. Strategies to modulate microRNA functions for the treatment of cancer or organ injury. Pharmacol Rev, 72(3):639-667.

[66]LiDF, LiuJ, GuoBS, et al., 2016. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat Commun, 7:10872.

[67]LiDM, ZhangRX, SunQY, et al., 2020. Involvement of Bmal1 and circadian clock signaling in chondrogenic differentiation of ATDC5 cells by fluoride. Ecotoxicol Environ Saf, 204:111058.

[68]LiJ, XueK, ZhengY, et al., 2019. RORA overexpression alleviates nasal mucosal injury and enhances red blood cell immune adhesion function in a mouse model of allergic rhinitis via inactivation of the Wnt/β‍-catenin signaling pathway. Int Arch Allergy Immunol, 180(2):79-90.

[69]LiJC, ZouXM, 2019. MiR-652 serves as a prognostic biomarker in gastric cancer and promotes tumor proliferation, migration, and invasion via targeting RORA. Cancer Biomark, 26(3):323-331.

[70]LiXG, LiuN, GuB, et al., 2018. BMAL1 regulates balance of osteogenic-osteoclastic function of bone marrow mesenchymal stem cells in type 2 diabetes mellitus through the NF-‍κB pathway. Mol Biol Rep, 45(6):‍1691-1704.

[71]LinJM, KilmanVL, KeeganK, et al., 2002. A role for casein kinase 2α in the Drosophila circadian clock. Nature, 420(6917):816-820.

[72]LiuC, KelnarK, LiuBG, et al., 2011. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med, 17(2):211-215.

[73]LiuQ, WuYY, YoshizawaT, et al., 2016. Basic helix-loop-helix transcription factor DEC2 functions as an anti-apoptotic factor during paclitaxel-induced apoptosis in human prostate cancer cells. Int J Mol Med, 38(6):1727-1733.

[74]LiuQ, WuYY, SeinoH, et al., 2018. Correlation between DEC1/DEC2 and epithelial-mesenchymal transition in human prostate cancer PC3-cells. Mol Med Rep, 18(4):3859-3865.

[75]LouJ, WangYL, ZhangZM, et al., 2017. Activation of MMPs in macrophages by Mycobacterium tuberculosis via the miR-223-BMAL1 signaling pathway. J Cell Biochem, 118(12):4804-4812.

[76]LuanX, TianXY, ZhangHX, et al., 2019. Exercise as a prescription for patients with various diseases. J Sport Health Sci, 8(5):422-441.

[77]LuchavovaM, ZikanV, MichalskaD, et al., 2011. The effect of timing of teriparatide treatment on the circadian rhythm of bone turnover in postmenopausal osteoporosis. Eur J Endocrinol, 164(4):643-648.

[78]MaS, WangDD, MaCY, et al., 2019. MicroRNA-96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the Wnt signaling pathway by binding to SOST. J Cell Biochem, 120(9):15429-15442.

[79]MaoXF, LiXG, HuW, et al., 2020. Downregulated brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 inhibits osteogenesis of BMSCs through p53 in type 2 diabetes mellitus. Biol Open, 9(7):bio051482.

[80]MaoZX, ZhuYH, HaoWM, et al., 2019. MicroRNA-155 inhibition up-regulates LEPR to inhibit osteoclast activation and bone resorption via activation of AMPK in alendronate-treated osteoporotic mice. IUBMB Life, 71(12):1916-1928.

[81]MarondeE, SchillingAF, SeitzS, et al., 2010. The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation. PLoS ONE, 5(7):e11527.

[82]MenetJS, PescatoreS, RosbashM, 2014. CLOCK:BMAL1 is a pioneer-like transcription factor. Genes Dev, 28(1):8-13.

[83]MichouL, 2018. Epigenetics of bone diseases. Joint Bone Spine, 85(6):701-707.

[84]MinHY, KimKM, WeeG, et al., 2016. Bmal1 induces osteoblast differentiation via regulation of BMP2 expression in MC3T3-E1 cells. Life Sci, 162:41-46.

[85]MohrAM, MottJL, 2015. Overview of microRNA biology. Semin Liver Dis, 35(1):3-11.

[86]MollazadehS, BazzazBSF, NeshatiV, et al., 2019. Overexpression of microRNA-148b-3p stimulates osteogenesis of human bone marrow-derived mesenchymal stem cells: the role of microRNA-148b-3p in osteogenesis. BMC Med Genet, 20:117.

[87]NagaoS, IwataN, SoejimaY, et al., 2019. Interaction of ovarian steroidogenesis and clock gene expression modulated by bone morphogenetic protein-7 in human granulosa cells. Endocr J, 66(2):157-164.

[88]NeudeckerV, BrodskyKS, KrethS, et al., 2016. Emerging roles for microRNAs in perioperative medicine. Anesthesiology, 124(2):489-506.

[89]NeudeckerV, ColganSP, EltzschigHK, 2017. Novel therapeutic concepts for inflammatory bowel disease—from bench to bedside. J Mol Med (Berl), 95(9):899-903.

[90]PatkeA, MurphyPJ, OnatOE, et al., 2017. Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. Cell, 169(2):203-215.e13.

[91]PawlakD, DomaniewskiT, ZnorkoB, et al., 2017. The impact of peripheral serotonin on leptin-brain serotonin axis, bone metabolism and strength in growing rats with experimental chronic kidney disease. Bone, 105:1-10.

[92]QuevedoI, ZunigaAM, 2010. Low bone mineral density in rotating-shift workers. J Clin Densitom, 13(4):467-469.

[93]RageulJ, ParkJJ, ZengPP, et al., 2020. SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks. Nat Commun, 11:5495.

[94]RayS, ValekunjaUK, StangherlinA, et al., 2020. Circadian rhythms in the absence of the clock gene Bmal1. Science, 367(6479):800-806.

[95]RealeME, WebbIC, WangX, et al., 2013. The transcription factor Runx2 is under circadian control in the suprachiasmatic nucleus and functions in the control of rhythmic behavior. PLoS ONE, 8(1):e54317.

[96]RuanW, YuanXY, EltzschigHK, 2021. Circadian rhythm as a therapeutic target. Nat Rev Drug Discov, 20(4):287-307.

[97]SamsaWE, VasanjiA, MiduraRJ, et al., 2016. Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype. Bone, 84:194-203.

[98]SatoF, KohsakaA, BhawalUK, et al., 2018. Potential roles of Dec and BMAL1 genes in interconnecting circadian clock and energy metabolism. Int J Mol Sci, 19(3):781.

[99]SchiblerU, 2005. The daily rhythms of genes, cells and organs. Biological clocks and circadian timing in cells. EMBO Rep, 6:S9-S13.

[100]SchiblerU, RippergerJ, BrownSA, 2003. Peripheral circadian oscillators in mammals: time and food. J Biol Rhythms, 18(3):250-260.

[101]SchilperoortM, BravenboerN, LimJ, et al., 2020. Circadian disruption by shifting the light-dark cycle negatively affects bone health in mice. FASEB J, 34(1):1052-1064.

[102]SchirleNT, Sheu-GruttadauriaJ, MacraeIJ, 2014. Structural basis for microRNA targeting. Science, 346(6209):608-613.

[103]SelfridgeJM, GotohT, SchiffhauerS, et al., 2016. Chronotherapy: intuitive, sound, founded... but not broadly applied. Drugs, 76(16):1507-1521.

[104]ShiJF, TongRY, ZhouM, et al., 2022. Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation. Eur Heart J, 43(24):2317-2334.

[105]SmithSS, DoleNS, FranceschettiT, et al., 2016. MicroRNA-433 dampens glucocorticoid receptor signaling, impacting circadian rhythm and osteoblastic gene expression. J Biol Chem, 291(41):21717-21728.

[106]SongC, TanP, ZhangZ, et al., 2018. REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation. FASEB J, 32(6):3215-3228.

[107]SulliG, ManoogianENC, TaubPR, et al., 2018. Training the circadian clock, clocking the drugs, and drugging the clock to prevent, manage, and treat chronic diseases. Trends Pharmacol Sci, 39(9):812-827.

[108]SunMG, HuLQ, WangS, et al., 2020. Circulating microRNA-19b identified from osteoporotic vertebral compression fracture patients increases bone formation. J Bone Miner Res, 35(2):306-316.

[109]SunX, GuoQ, WeiWH, et al., 2019. Current progress on microRNA-based gene delivery in the treatment of osteoporosis and osteoporotic fracture. Int J Endocrinol, 2019:6782653.

[110]SunXM, DongolS, QiuCP, et al., 2018. miR-652 promotes tumor proliferation and metastasis by targeting RORA in endometrial cancer. Mol Cancer Res, 16(12):1927-1939.

[111]SunYQ, KuekV, LiuYH, et al., 2019. MiR-214 is an important regulator of the musculoskeletal metabolism and disease. J Cell Physiol, 234(1):231-245.

[112]SwansonCM, SheaSA, WolfeP, et al., 2017. Bone turnover markers after sleep restriction and circadian disruption: a mechanism for sleep-related bone loss in humans. J Clin Endocrinol Metab, 102(10):3722-3730.

[113]TaipaleenmäkiH, 2018. Regulation of bone metabolism by microRNAs. Curr Osteoporos Rep, 16(1):1-12.

[114]TakaradaT, XuC, OchiH, et al., 2017. Bone resorption is regulated by circadian clock in osteoblasts. J Bone Miner Res, 32(4):872-881.

[115]TangZH, XuTY, LiYH, et al., 2020. Inhibition of CRY2 by STAT3/miRNA-7-5p promotes osteoblast differentiation through upregulation of CLOCK/BMAL1/P300 expression. Mol Ther Nucleic Acids, 19:865-876.

[116]TongXY, ChenX, ZhangSH, et al., 2019. The effect of exercise on the prevention of osteoporosis and bone angiogenesis. Biomed Res Int, 2019:8171897.

[117]TsangK, LiuHM, YangY, et al., 2019. Defective circadian control in mesenchymal cells reduces adult bone mass in mice by promoting osteoclast function. Bone, 121:172-180.

[118]UlbingM, KirschAH, LeberB, et al., 2017. MicroRNAs 223-3p and 93-5p in patients with chronic kidney disease before and after renal transplantation. Bone, 95:115-123.

[119]WangBX, YangJK, FanLJ, et al., 2021. Osteogenic effects of antihypertensive drug benidipine on mouse MC3T3-E1 cells in vitro. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(5):410-420.

[120]WangQ, WangCH, MengY, 2019. MicroRNA-1297 promotes the progression of osteoporosis through regulation of osteogenesis of bone marrow mesenchymal stem cells by targeting WNT5A. Eur Rev Med Pharmacol Sci, 23(11):4541-4550.

[121]WangS, LiF, LinYK, et al., 2020. Targeting REV-ERBα for therapeutic purposes: promises and challenges. Theranostics, 10(9):4168-4182.

[122]WelzPS, ZinnaVM, SymeonidiA, et al., 2019. BMAL1-driven tissue clocks respond independently to light to maintain homeostasis. Cell, 177(6):1436-1447.e12.

[123]WuQY, WangJ, TongX, et al., 2019. Emerging role of circadian rhythm in bone remodeling. J Mol Med (Berl), 97(1):19-24.

[124]XieY, ZhangLH, GaoYP, et al., 2015. The multiple roles of microRNA-223 in regulating bone metabolism. Molecules, 20(10):19433-19448.

[125]XuC, OchiH, FukudaT, et al., 2016. Circadian clock regulates bone resorption in mice. J Bone Miner Res, 31(7):1344-1355.

[126]XueYB, ZhangY, 2018. Emerging roles for microRNA in the regulation of Drosophila circadian clock. BMC Neurosci, 19:1.

[127]YangN, SmyllieNJ, MorrisH, et al., 2020. Quantitative live imaging of venus::BMAL1 in a mouse model reveals complex dynamics of the master circadian clock regulator. PLoS Genet, 16(4):e1008729.

[128]YangXM, WoodPA, OhEY, et al., 2009. Down regulation of circadian clock gene Period 2 accelerates breast cancer growth by altering its daily growth rhythm. Breast Cancer Res Treat, 117(2):423-431.

[129]YuanGS, HuaBX, YangY, et al., 2017. The circadian gene Clock regulates bone formation via PDIA3. J Bone Miner Res, 32(4):861-871.

[130]YuanY, ZhangLL, TongXY, et al., 2017. Mechanical stress regulates bone metabolism through microRNAs. J Cell Physiol, 232(6):1239-1245.

[131]YuanY, GuoJM, ZhangLL, et al., 2019. MiR-214 attenuates the osteogenic effects of mechanical loading on osteoblasts. Int J Sports Med, 40(14):931-940.

[132]YueDX, ZhaoJJ, ChenHZ, et al., 2020. MicroRNA-7, synergizes with RORα, negatively controls the pathology of brain tissue inflammation. J Neuroinflammation, 17:28.

[133]YueJ, HeJJ, WeiYJ, et al., 2020. Decreased expression of Rev-Erbα in the epileptic foci of temporal lobe epilepsy and activation of Rev-Erbα have anti-inflammatory and neuroprotective effects in the pilocarpine model. J Neuroinflammation, 17:43.

[134]ZhangB, LiYL, YuY, et al., 2018. MicroRNA-378 promotes osteogenesis-angiogenesis coupling in BMMSCs for potential bone regeneration. Anal Cell Pathol (Amst), 2018:8402390.

[135]ZhangD, WuYF, LiZH, et al., 2021. MiR-144-5p, an exosomal miRNA from bone marrow-derived macrophage in type 2 diabetes, impairs bone fracture healing via targeting Smad1. J Nanobiotechnology, 19:226.

[136]ZhangYC, LiSY, YuanSJ, et al., 2019. MicroRNA-23a inhibits osteogenesis of periodontal mesenchymal stem cells by targeting bone morphogenetic protein signaling. Arch Oral Biol, 102:93-100.

[137]ZhengHJ, LiuJ, TycksenE, et al., 2019. MicroRNA-181a/b-1 over-expression enhances osteogenesis by modulating PTEN/PI3K/AKT signaling and mitochondrial metabolism. Bone, 123:92-102.

[138]ZhouL, HeJ, SunSW, et al., 2019. Cryptochrome 1 regulates osteoblast differentiation via the AKT kinase and extracellular signal-regulated kinase signaling pathways. Cell Reprogram, 21(3):141-151.

[139]ZhouX, YuR, LongYL, et al., 2018. BMAL1 deficiency promotes skeletal mandibular hypoplasia via OPG downregulation. Cell Prolif, 51(5):e12470.

[140]ZhuSP, YaoF, QiuH, et al., 2018. Coupling factors and exosomal packaging microRNAs involved in the regulation of bone remodelling. Biol Rev, 93(1):469-480.

[141]ZhuoHY, WangYH, ZhaoQ, 2018. The interaction between Bmal1 and Per2 in mouse BMSC osteogenic differentiation. Stem Cells Int, 2018:3407821.

[142]ZouYJ, LinX, BuJG, et al., 2020. Timeless-stimulated miR-5188-FOXO1/β‍-catenin-c-Jun feedback loop promotes stemness via ubiquitination of β‍-catenin in breast cancer. Mol Ther, 28(1):313-327.

[143]ZvonicS, PtitsynAA, KilroyG, et al., 2007. Circadian oscillation of gene expression in murine calvarial bone. J Bone Miner Res, 22(3):357-365.