Review articleThe biological function of BMAL1 in skeleton development and disorders
Graphical abstract
Introduction
The skeleton is highly hard and has a lot of important functions including structural support, movement and protection for key organs. And the bone has numerous shapes including flat, long, and curved, which determines its function. The skeleton is the most important reservoir of calcium, phosphate and other minerals, which could regulate the mineral homeostasis [1]. The skeleton is characterized by bone and cartilage which are produced by osteoblasts and chondrocytes respectively. Mesenchymal stem cells are pluripotent cells, which can differentiate along the osteoblastic, chondrocytic, adipocytic, fibroblastic lineages and so on [2]. During Embryonic development, bone forms via two processes that intramembranous and endochondral ossification. Teeth are similar to bones, whose formation is triggered by dental epithelium and mesenchyme condense [3]. This process is mainly regulated by signaling pathways of bone morphogenic protein (BMP), Wnt, hedgehog and fibroblast growth factor (FGF) [4,5].
The circadian clock system is an endogenous regulator and serves to synchronize the individual physiology function and behavior across the body so that mammals can adapt to the stress and events from the environment. The central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The retina senses the light signal and synchronizes the molecular clock of SCN, which then orchestrates the peripheral clock in all organs and cells, including osteoblasts, osteoclasts and chondrocytes [[6], [7], [8]]. A transcriptional feedback mechanism controls this process where period is about 24 h [9,10]. The basic helix-loop-helix and PER-ARNTL-SIM (bHLH-PAS) protein brain and muscle Arnt-like protein 1 (BMAL1) is critical to this circadian oscillator [11,12]. It has been confirmed that circadian locomotor output cycles kaput (CLOCK) can interact with BMAL1 forming a heterodimer which binds to clock-controlled genes (CCGs) containing E-box element and activates their transcription [13,14]. In addition, Period (Per) and Cryptochrome (Cry) are core clock genes as well, whose transcription are initiated by BMAL1/CLOCK heterodimer. Interestingly, PER and CRY can inhibit the transcription of Bmal1 and Clock in turn and thus a negative feedback loop formed. In addition, nuclear receptors (REV-ERB) and RAR-related orphan receptor (ROR) whose transcription are regulated by BMAL1 are involved in the accessory loop. In turn REV-ERBs, or RORs inhibits and enhances BMAL1 transcription respectively [15] (Fig. 1).
Multiple biological processes could control the protein levels and function of BMAL1. During development, the specific expression pattern of BMAL1 is regulated by hormones, cytokines and non-coding RNA including, glucocorticoids, melatonin, insulin-like growth factor (IGF) and microRNA [6,7,16,17]. Bmal1, as a core clock gene, is expressed widespread in skeletal related cells that from mesenchymal stem cells to the terminal differentiated osteocytes and chondrocytes (Fig. 2). Over decades, more and more researches have revealed the relationship between BMAL1 and skeleton development. It has been certificated that BMAL1 could influence numerous factors critical to skeletal and tooth development, such as RUNX2, SOX9, Wnt signaling pathway, BMP signaling pathway and Hedgehog signaling pathway [[18], [19], [20]]. It has been reported that Bmal1 displayed a strong oscillatory profile, whose zenith at ZT0 and nadir at ZT12 in bone tissues [21]. By coincidence, evidence showed that the bone formation process occurs primarily at night, which is consistent with the expression peak time of BMAL1. Above these can be further explained why it is important to emphasize the function of BMAL1 in skeletal tissues. Therefore, in this review, we systemically describe the essential role and underlying mechanisms of circadian regulator BMAL1 in hard tissue development, including bone, cartilage and teeth, and devote to summarize its potential value in searching new therapeutic strategy for bone disorders.
Section snippets
BMAL1 is critical for osteoblast differentiation and bone formation
In craniofacial skeleton and the clavicle, bone forms mainly through intramembranous ossification in which mesenchymal condensations directly differentiate into osteoblasts and deposit matrix rich in type I collagen [22,23]. Eventually osteocytes are embedded in the bone matrix, which are terminally differentiated state from osteoblasts [24]. BMAL1 is necessary for embryonic development and intramembranous ossification since loss of BMAL1 in mice impaired bone formation and produced a low bone
The role of BMAL1 in chondrogenesis and cartilage development
During endochondral ossification, the mesenchymal precursor cell condensations differentiate into chondrocytes, which produce an avascular cartilage model. The perichondrium is formed by the cells at the edge of condensations [64]. These epiphyseal chondrocytes of the cartilage templates undergo rapid proliferation, matrix secretion and progressive maturation. As the cartilage developing, the chondrocytes differentiate into non-proliferative hypertrophic phenotype. The hypertrophic chondrocytes
BMAL1 regulates osteoclast differentiation and bone resorption
The growth and maintenance of bone undergo continual remodeling which depends on the sequential effort of the coupling of osteoblasts and osteoclasts [86]. Osteoclasts, which are critical to bone metabolism, are multinucleate giant cells derived from monocyte/macrophage haematopoietic lineage. The differentiation progress of preosteoclasts cells to osteoclast is under control of two key cytokines that macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB-ligand (RANKL) [87
Circadian protein BMAL1 is indispensable in dental development
Tooth, as a hard tissue consists of dental enamel and dentin, which is similar to bone tissues and is formed by ameloblasts and odontoblasts. The cross-striation widely exists along the length of enamel prisms, which is related to a 24-hour circadian rhythm in enamel matrix apposition [[95], [96], [97]]. This phenomenon suggests that circadian clock is connected with teeth formation. And it has been certificated that the tooth-forming cells, including ameloblast and odontoblast are controlled
The interaction between circadian clock and bone remodeling trigger
Important unresolved issues including, whether and how BMAL1 interacts with numerous stimuli, including metabolic responses and mechanical stimuli, which can trigger bone remodeling. The osteocytes network can detect mechanical loading and extracellular ion concentration. Animal experiments showed that maxillary expansion was greater when orthodontic force was administrated during the daytime where more bone formed in tension area and more osteoclasts on the pressure side [104,105]. In
Osteoarthritis
Osteoarthritis (OA) is an age-related disease, which can cause disability and reduce life quality [116,117]. However, the reasons for OA are not fully understood and even without any causes, the disease still takes place which is referring primary OA. There is a higher prevalence of OA because of the increasing population aging, obesity and joint injury, all of which are risk factor of this disease [[118], [119], [120]]. The available studies suggest that the OA pathogenesis manifests through
Conclusions
This systematic review indicated that BMAL1 participated in the multiple biological processes during the development and remodeling of bone and teeth. At the cellular level, BMAL1 regulates the growth, differentiation and function of bone-related cells. BMAL1 also can interact with mechanical and metabolic needs triggering bone remodeling, while the mechanisms still remain unknown. Furthermore, preclinical studies suggest that BMAL1 abnormality is associated with bone hypoplasia and age-related
Abbreviations
- ALP
alkaline phosphatase
- Amelx
amelogenin X-Linked
- bHLH-PAS
basic helix-loop-helix and PER-ARNTL-SIM
- BMAL1
brain and muscle Arnt-like protein 1
- BMP
bone morphogenic protein
- Car2
carbonic anhydrase 2
- CaSR
calcium-sensing receptor
- CCGs
clock-controlled genes
- CLOCK
circadian locomotor output cycles kaput
- Col10a1
collagen type X
- FGF
fibroblast growth factor
- Gli1
glioma-associated oncogene
- GSK-3β
glycogen synthase kinase-3β
- Id1
inhibitor of DNA binding
- IGF
insulin-like growth factor
- Ihh
Indian hedgehog
- Klk4
kallikrein-related
Declaration of competing interest
The authors declare that there is no conflict of interest.
Acknowledgements
This work was supported by the National Science Foundation for Distinguished Young Scholars of China (31725011 to L.C.) and Health Commission of Hubei Province (WJ2019C001 to L.C.).
References (135)
- et al.
Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders
The Lancet Diabetes & Endocrinology
(2014) Molecular genetics of tooth development
Curr. Opin. Genet. Dev.
(2009)- et al.
Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes
Bone
(2014) Molecular bases for circadian clocks
Cell
(1999)- et al.
Mop3 is an essential component of the master circadian pacemaker in mammals
Cell
(2000) - et al.
MicroRNA-433 dampens glucocorticoid receptor signaling, impacting circadian rhythm and osteoblastic gene expression
J. Biol. Chem.
(2016) - et al.
Clock genes influence gene expression in growth plate and endochondral ossification in mice
J. Biol. Chem.
(2012) - et al.
The development of tissue-engineered bone of different origin through endochondral and intramembranous ossification following the implantation of mesenchymal stem cells and osteoblasts in a murine model
Biomaterials
(2010) - et al.
Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype
Bone
(2016) - et al.
BMAL1 deficiency contributes to mandibular dysplasia by upregulating MMP3
Stem Cell Reports
(2018)
Characterization of bone marrow-derived mesenchymal stem cells in aging
Bone
Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development
Cell
Runx2: structure, function, and phosphorylation in osteoblast differentiation
Int. J. Biol. Macromol.
The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation
Cell
Transcription factors in bone: developmental and pathological aspects
Trends Mol. Med.
Bmal1 induces osteoblast differentiation via regulation of BMP2 expression in MC3T3-E1 cells
Life Sci.
Adipogenesis and WNT signalling
Trends Endocrinol Metab
Defective circadian control in mesenchymal cells reduces adult bone mass in mice by promoting osteoclast function
Bone
Bone development
Bone
MSX2 stimulates chondrocyte maturation by controlling Ihh expression
J. Biol. Chem.
Molecular mechanism of hypoxia-induced chondrogenesis and its application in in vivo cartilage tissue engineering
Biomaterials
Targeting TGFbeta signaling in subchondral bone and articular cartilage homeostasis
Trends Pharmacol. Sci.
Osteoclasts: more than ‘bone eaters’
Trends Mol. Med.
The molecular clock mediates leptin-regulated bone formation
Cell
Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts
Dev. Cell
The tick tock of odontogenesis
Exp. Cell Res.
Circadian rhythms regulate amelogenesis
Bone
Marrow stromal stem cells
J. Clin. Invest.
Cell fate determination during tooth development and regeneration
Birth Defects Research Part C, Embryo Today: Reviews
The non-canonical BMP and Wnt/beta-catenin signaling pathways orchestrate early tooth development
Development (Cambridge, England)
Circadian production of melatonin in cartilage modifies rhythmic gene expression
J. Endocrinol.
Comparison of beta-adrenergic and glucocorticoid signaling on clock gene and osteoblast-related gene expressions in human osteoblast
Chronobiol. Int.
Circadian clocks: not your grandfather’s clock
Science (New York, N.Y.)
BMAL1-driven tissue clocks respond independently to light to maintain homeostasis
Cell
Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex
Science (New York, N.Y.)
Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA
Cell Res.
Genomics of circadian rhythms in health and disease
Genome Medicine
The physiological role of growth hormone and insulin-like growth factors
Orv. Hetil.
The circadian molecular clock creates epidermal stem cell heterogeneity
Nature
Deletion of clock gene Bmal1 impaired the chondrocyte function due to disruption of the HIF1alpha-VEGF signaling pathway
Cell Cycle (Georgetown, Tex)
BMAL1 gene regulates the osteogenic differentiation of bone marrow mesenchymal stem cells
Hua Xi Kou Qiang Yi Xue Za Zhi = Huaxi Kouqiang Yixue Zazhi = West China Journal of Stomatology
Bone development and remodeling in metabolic disorders
J. Inherit. Metab. Dis.
Static and dynamic osteogenesis: two different types of bone formation
Anat. Embryol.
Micro-CT observation of in vivo temporal change in mandibular condyle morphology in BMAL1 knockout mice
J. Oral Sci.
Mesenchymal stem cells: cell fate decision to osteoblast or adipocyte and application in osteoporosis treatment
Int. J. Mol. Sci.
Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis
Nat. Genet.
Osteogenesis and aging: lessons from mesenchymal stem cells
Stem Cell Res Ther
Microenvironmental views on mesenchymal stem cell differentiation in aging
J. Dent. Res.
Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock
Genes Dev.
Age-related BMAL1 change affects mouse bone marrow stromal cell proliferation and osteo-differentiation potential
Archives of Medical Science: AMS
Cited by (0)
- 1
Guangjin Chen and Qingming Tang contributed equally to this review.