Elsevier

Life Sciences

Volume 253, 15 July 2020, 117636
Life Sciences

Review article
The biological function of BMAL1 in skeleton development and disorders

https://doi.org/10.1016/j.lfs.2020.117636Get rights and content

Highlights

  • BMAL1 participates in multiple biological processes of skeleton development.

  • Circadian rhythm can interact with mechanical and metabolic stimuli regulating bone remodeling.

  • BMAL1 abnormality is associated with human skeletal disorders.

  • BMAL1 may be the therapeutic and preventive target of skeletal diseases.

Abstract

BMAL1 is a core component of the circadian clock loop, which directs the sophisticated circadian expression of clock-controlled genes. Skeletal Bone development is a complex biological process involving intramembranous ossification, endochondral ossification and bone remodeling, as well as specific cells, such as mesenchymal cells, osteoblasts, osteoclasts, chondrocytes, etc. Growing evidences suggest that BMAL1 is indispensable for hard tissue development, including bone, cartilage and teeth. Loss of BMAL1 in animals can inhibit bone and cartilage development, and result in abnormal bone mass. In mesenchymal cells, BMAL1 defect inhibits osteoblastic and chondrocytic differentiation. Inactivation of BMAL1 also can promote the differentiation and formation of osteoclasts and increase bone resorption. Specifically, preclinical data demonstrate that the abnormity of BMAL1 expression is associated with skeletal disorders such as skeletal mandibular hypoplasia, osteoarthritis, osteoporosis, etc. In this review, we systemically describe the impact of BMAL1 in skeletal development and homeostasis, and devote to searching new therapy strategies for bone disorders.

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.).

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    Guangjin Chen and Qingming Tang contributed equally to this review.

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