Circadian clock disruption stimulates bone loss via regulatory T cell-Mediated regulation of IL-10 expression.

Circadian rhythms play a crucial role in regulating various physiological processes, including specific immune functions that enhance the body's ability to anticipate and respond to threats effectively. However, research on the impact of circadian rhythms on osteoimmunology remains limited. Our study uncovered that circadian disruption leads to bone mass loss by reducing the population of Treg cells in the bone marrow. Furthermore, we observed a significant decrease in serum IL-10 cytokine levels in jet lagged mice. In our current investigation, we explored the anti-osteoclastogenic effects of IL-10 and found that IL-10 inhibits RANKL-induced osteoclastogenesis in a dose-dependent manner. Our findings suggest that the diminished anti-osteoclastogenic properties of Tregs under circadian disruption are mediated by IL-10 cytokine production. Moreover, our discoveries propose that administration of IL-10 or butyrate could potentially reverse bone mass loss in individuals experiencing jet lag.

Time of exercise differentially impacts bone growth in mice.

Although physical training has been shown to improve bone mass, the time of day to exercise for optimal bone growth remains uncertain. Here we show that engaging in physical activity during the early active phase, as opposed to the subsequent active or rest phase, results in a more substantial increase in bone length of male and female mice. Transcriptomic and metabolomic methodologies identify that exercise during the early active phase significantly upregulates genes associated with bone development and metabolism. Notably, oxidative phosphorylation-related genes show a rhythmic expression in the chondrification centre, with a peak at the early active phase, when more rhythmic genes in bone metabolism are expressed and bone growth is synergistically promoted by affecting oxidative phosphorylation, which is confirmed by subsequent pharmacological investigations. Finally, we construct a signalling network to predict the impact of exercise on bone growth. Collectively, our research sheds light on the intricacies of human exercise physiology, offering valuable implications for interventions.

The osteoclastic activity in apical distal region of molar mesial roots affects orthodontic tooth movement and root resorption in rats.

The utilization of optimal orthodontic force is crucial to prevent undesirable side effects and ensure efficient tooth movement during orthodontic treatment. However, the sensitivity of existing detection techniques is not sufficient, and the criteria for evaluating optimal force have not been yet established. Here, by employing 3D finite element analysis methodology, we found that the apical distal region (A-D region) of mesial roots is particularly sensitive to orthodontic force in rats. Tartrate-resistant acidic phosphatase (TRAP)-positive osteoclasts began accumulating in the A-D region under the force of 40 grams (g), leading to alveolar bone resorption and tooth movement. When the force reached 80 g, TRAP-positive osteoclasts started appearing on the root surface in the A-D region. Additionally, micro-computed tomography revealed a significant root resorption at 80 g. Notably, the A-D region was identified as a major contributor to whole root resorption. It was determined that 40 g is the minimum effective force for tooth movement with minimal side effects according to the analysis of tooth movement, inclination, and hyalinization. These findings suggest that the A-D region with its changes on the root surface is an important consideration and sensitive indicator when evaluating orthodontic forces for a rat model. Collectively, our investigations into this region would aid in offering valuable implications for preventing and minimizing root resorption during patients' orthodontic treatment.

Dental professionals' use of personal protective equipment during COVID-19: a cross-sectional study in China.

Background: Appropriate use of personal protective equipment (PPE) could significantly reduce the risk of viral transmission and infection. This study aimed to assess the use of PPE among dentists during the COVID-19 pandemic in China, explore its influencing factors, and provide some practical recommendations. Methods: An online cross-sectional survey was conducted among 384 Chinese dentists in September 2022. The questionnaire comprised a series of questions about demographic characteristics, compliance with proper PPE use, personal barriers to use, and exposure risk estimation. Results: Of the 384 respondents, 57.3% had unacceptable compliance with the proper use of PPE during COVID-19. Medical surgical mask is the most common for dental professionals to wear (93.8%), followed by goggles or face shield (63.8%), and isolation gown (53.1%). Unexpectedly, only 63.3% of respondents always change masks with guidelines. The condition for changing goggles/face shields and isolation gowns is even worse (45.6 and 37.0%, respectively). Visual barriers, physical discomfort, complex procedures, and heavy workload were the most common personal barriers to use. According to the results of Chi-square test and correlation analysis, PPE use compliance was associated with age, years of practice, medical institution type, and exposure risk estimation. Conclusion: Chinese dental professionals need to improve their compliance with the proper use of PPE, especially those in the 31-40 age group, with 11-15 experience years and working in private dental clinics. Increasing compliance with PPE may be achieved by addressing personal barriers to use, human resource shortages, and perceptions of exposure risk.

Developmental growth plate cartilage formation suppressed by artificial light at night via inhibiting BMAL1-driven collagen hydroxylation.

Exposure to artificial light at night (LAN) can induce obesity, depressive disorder and osteoporosis, but the pernicious effects of excessive LAN exposure on tissue structure are poorly understood. Here, we demonstrated that artificial LAN can impair developmental growth plate cartilage extracellular matrix (ECM) formation and cause endoplasmic reticulum (ER) dilation, which in turn compromises bone formation. Excessive LAN exposure induces downregulation of the core circadian clock protein BMAL1, which leads to collagen accumulation in the ER. Further investigations suggest that BMAL1 is the direct transcriptional activator of prolyl 4-hydroxylase subunit alpha 1 (P4ha1) in chondrocytes, which orchestrates collagen prolyl hydroxylation and secretion. BMAL1 downregulation induced by LAN markedly inhibits proline hydroxylation and transport of collagen from ER to golgi, thereby inducing ER stress in chondrocytes. Restoration of BMAL1/P4HA1 signaling can effectively rescue the dysregulation of cartilage formation within the developmental growth plate induced by artificial LAN exposure. In summary, our investigations suggested that LAN is a significant risk factor in bone growth and development, and a proposed novel strategy targeting enhancement of BMAL1-mediated collagen hydroxylation could be a potential therapeutic approach to facilitate bone growth.

F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production.

BACKGROUND: Tumor-resident microbiota has been documented for various cancer types. Oral squamous cell carcinoma (OSCC) is also enriched with microbiota, while the significance of microbiota in shaping the OSCC microenvironment remains elusive. METHODS: We used bioinformatics and clinical sample analysis to explore relationship between F. nucleatum and OSCC progression. Xenograft tumor model, metabolic screening and RNA sequencing were performed to elucidate mechanisms of pro-tumor role of F. nucleatum. FINDINGS: We show that a major protumorigenic bacterium, F. nucleatum, accumulates in invasive margins of OSCC tissues and drives tumor-associated macrophages (TAMs) formation. The mechanistic dissection shows that OSCC-resident F. nucleatum triggers the GalNAc-Autophagy-TBC1D5 signaling, leading to GLUT1 aggregation in the plasma membrane and the deposition of extracellular lactate. Simultaneous functional inhibition of GalNAc and GLUT1 efficiently reduces TAMs formation and restrains OSCC progression. INTERPRETATION: These findings suggest that tumor-resident microbiota affects the immunomodulatory and protumorigenic microenvironment via modulating glycolysis and extracellular lactate deposition. The targeted intervention of this process could provide a distinct clinical strategy for patients with advanced OSCC. FUNDING: This work was supported by the National Natural Science Foundation of China for Key Program Projects (82030070, to LC) and Distinguished Young Scholars (31725011, to LC), as well as Innovation Team Project of Hubei Province (2020CFA014, to LC).

Melatonin regulates the immune response and improves Sjögren's syndrome-like symptoms in NOD/Ltj Mice.

Primary Sjögren's syndrome (pSS) is an autoimmune disease that primarily affects exocrine glands and is characterized by sicca syndrome and systemic manifestation. Mounting evidence indicates that circadian clocks are involved in the onset and progression of autoimmune diseases, including rheumatic arthritis, multiple sclerosis, and systemic lupus erythematosus. However, few studies have reported the expression of clock genes in pSS. There is no ideal therapeutic method for pSS, the management of pSS is mainly palliative, aims to alleviate sicca symptoms. Melatonin is a neuroendocrine hormone mainly secreted by the pineal gland that plays an important role in the maintenance of the circadian rhythm and immunomodulation. Hence, this study aimed to analyse the circadian expression profile of clock genes in pSS, and further evaluate the therapeutic potential of melatonin in pSS. We discovered a distinct clock gene expression profile in the salivary glands of pSS patients and pSS animal model. More importantly, melatonin administration improved the hypofunction of the salivary glands, inhibited inflammatory development, and regulated clock gene expression in animal model of pSS. Our study suggested that the pathogenesis of pSS might correlate with abnormal expression of circadian genes, and that melatonin might be a potential candidate for prevention and treatment of pSS.

Circadian rhythm modulates endochondral bone formation via MTR1/AMPKß1/BMAL1 signaling axis.

The circadian clock is a master regulator in coordinating daily oscillations of physiology and behaviors. Nevertheless, how the circadian rhythm affects endochondral ossification is poorly understood. Here we showed that endochondral bone formation exhibits circadian rhythms, manifested as fast DNA replication in the daytime, active cell mitosis, and matrix synthesis at night. Circadian rhythm disruption led to endochondral ossification deformities. The mechanistic dissection revealed that melatonin receptor 1 (MTR1) periodically activates the AMPKß1 phosphorylation, which then orchestrates the rhythms of cell proliferation and matrix synthesis via destabilizing the clock component CRY1 and triggering BMAL1 expression. Accordingly, the AMPKß1 agonist is capable of alleviating the abnormity of endochondral ossification caused by circadian dysrhythmias. Taken together, these findings indicated that the central circadian clock could control endochondral bone formation via the MTR1/AMPKß1/BMAL1 signaling axis in chondrocytes. Also, our results suggested that the AMPKß1 signaling activators are promising medications toward endochondral ossification deformities.

PLAU Promotes Cell Proliferation and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma.

Plasminogen activator, urokinase (uPA) is a secreted serine protease whose Dysregulation is often accompanied by various cancers. However, the biological functions and potential mechanisms of PLAU in head and neck squamous cell carcinoma (HNSCC) remain undetermined. Here, the expression, prognosis, function, and coexpression genetic networks of PLAU in HNSCC were investigated by a series of public bioinformatics tools. A Higher PLAU level predicted a poorer clinical outcome. Meanwhile, functional network analysis implied that PLAU and associated genes mainly regulated cell-substrate adhesion, tissue migration, and extracellular matrix binding. The top 4 significantly associated genes are C10orf55, ITGA5, SERPINE1, and TNFRSF12A. Pathway enrichment analysis indicated that PLAU might activate the epithelial-to-mesenchymal transition (EMT) process, which could explain the poor prognosis in HNSCC. Besides, genes associated with PLAU were also enriched in EMT pathways. We further validated the bioinformatics analysis results by in vivo and in vitro experiments. Then, we found that much more PLAU was detected in HNSCC tissues, and the silencing of PLAU inhibit the proliferation, migration, and EMT process of CAL27 cell lines. Notably, the downregulation of PLAU decreased the expression of TNFRSF12A. Moreover, knockdown TNFRSF12A also inhibits cell proliferation and migration. In vivo experiment results indicated that PLAU inhibition could suppress tumor growth. Collectively, PLAU is necessary for tumor progression and can be a diagnostic and prognostic biomarker in HNSCC.

Insight into the roles of melatonin in bone tissue and bone­related diseases (Review).

Bone­related diseases comprise a large group of common diseases, including fractures, osteoporosis and osteoarthritis (OA), which affect a large number of individuals, particularly the elderly. The progressive destruction and loss of alveolar bone caused by periodontitis is a specific type of bone loss, which has a high incidence and markedly reduces the quality of life of patients. With the existing methods of prevention and treatment, the incidence and mortality of bone­related diseases are still gradually increasing, creating a significant financial burden to societies worldwide. To prevent the occurrence of bone­related diseases, delay their progression or reverse the injuries they cause, new alternative or complementary treatments need to be developed. Melatonin exerts numerous physiological effects, including inducing anti­inflammatory and antioxidative functions, resetting circadian rhythms and promoting wound healing and tissue regeneration. Melatonin also participates in the health management of bone and cartilage. In the present review, the potential roles of melatonin in the pathogenesis and progression of bone injury, osteoporosis, OA and periodontitis are summarized. Furthermore, the high efficiency and diversity of the physiological regulatory effects of melatonin are highlighted and the potential benefits of the use of melatonin for the clinical prevention and treatment of bone­related diseases are discussed.

Bmal1 Regulates Coagulation Factor Biosynthesis in Mouse Liver in Streptococcus oralis Infection.

Streptococcus oralis (S. oralis) has been recognized as a fatal pathogen to cause multiorgan failure by contributing to the formation of microthrombus. Coagulation and fibrinolysis systems have been found under the control of circadian clock genes. This study aimed to explore the correlation between BMAL1 and coagulation factor biosynthesis in S. oralis infection. Mice were administered S. oralis to induce sepsis, and HepG2 cells were also infected by S. oralis. The expression of BMAL1 of hepatocytes was downregulated in the S. oralis infection group, leading to the downregulation of coagulation factor VII (FVII) and the upregulation of the coagulation factor XII (FXII) in vitro and in vivo. Furthermore, we confirmed that the deficiency of BAML1 contributed to the elevation of FVII and the decline in FXII by constructing BMAL1-deficiency (Bmal1-/-) mice. The current result showed that BMAL1 regulates FVII directly. Thus, a novel insight into the coagulation abnormality in S. oralis infection was gained that may optimize the treatment of sepsis by rescuing the expression of BMAL1 in the liver.

Porphyromonas gingivalis disrupts vascular endothelial homeostasis in a TLR-NF-κB axis dependent manner.

Cardiovascular disease is still the leading cause of mortality worldwide. Vascular endothelial dysfunction is viewed as the initial step of most cardiovascular diseases. Many studies have indicated that periodontal pathogens, especially Porphyromonas gingivalis, are closely correlated with vascular endothelial homeostasis, but the function of P. gingivalis and the underlying mechanisms are still elusive. To illuminate the effects and elucidate the mechanisms of P. gingivalis on endothelial structural integrity, we developed P. gingivalis infection models in vivo and in vitro. Endothelial cell proliferation, differentiation and apoptosis were detected. Here, we showed that P. gingivalis can impair endothelial integrity by inhibiting cell proliferation and inducing endothelial mesenchymal transformation and apoptosis of endothelial cells, which reduce the cell levels and cause the endothelium to lose its ability to repair itself. A mechanistic analysis showed that TLR antagonist or NF-κB signalling inhibitor can largely rescue the damaged integrity of the endothelium caused by P. gingivalis, suggesting that TLR-NF-κB signalling plays a vital role in vascular endothelial homeostasis destroyed by P. gingivalis. These results suggest a potential intervention method for the prevention and treatment of cardiovascular disease.

Role of the oral microbiota in cancer evolution and progression.

Bacteria identified in the oral cavity are highly complicated. They include approximately 1000 species with a diverse variety of commensal microbes that play crucial roles in the health status of individuals. Epidemiological studies related to molecular pathology have revealed that there is a close relationship between oral microbiota and tumor occurrence. Oral microbiota has attracted considerable attention for its role in in-situ or distant tumor progression. Anaerobic oral bacteria with potential pathogenic abilities, especially Fusobacterium nucleatum and Porphyromonas gingivalis, are well studied and have close relationships with various types of carcinomas. Some aerobic bacteria such as Parvimonas are also linked to tumorigenesis. Moreover, human papillomavirus, oral fungi, and parasites are closely associated with oropharyngeal carcinoma. Microbial dysbiosis, colonization, and translocation of oral microbiota are necessary for implementation of carcinogenic functions. Various underlying mechanisms of oral microbiota-induced carcinogenesis have been reported including excessive inflammatory reaction, immunosuppression of host, promotion of malignant transformation, antiapoptotic activity, and secretion of carcinogens. In this review, we have systemically described the impact of oral microbial abnormalities on carcinogenesis and the future directions in this field for bringing in new ideas for effective prevention of tumors.

The biological function of BMAL1 in skeleton development and disorders.

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.

BMAL1-Downregulation Aggravates Porphyromonas Gingivalis-Induced Atherosclerosis by Encouraging Oxidative Stress.

RATIONALE: Atherosclerotic cardiovascular diseases are the leading cause of mortality worldwide. Atherosclerotic cardiovascular diseases are considered as chronic inflammation processes. In addition to risk factors associated with the cardiovascular system itself, pathogenic bacteria such as the periodontitis-associated Porphyromonas gingivalis (P gingivalis) are also closely correlated with the development of atherosclerosis, but the underlying mechanisms are still elusive. OBJECTIVE: To elucidate the mechanisms of P gingivalis-accelerated atherosclerosis and explore novel therapeutic strategies of atherosclerotic cardiovascular diseases. METHODS AND RESULTS: Bmal1-/- (brain and muscle Arnt-like protein 1) mice, ApoE-/- mice, Bmal1-/-ApoE-/- mice, conditional endothelial cell Bmal1 knockout mice (Bmal1fl/fl; Tek-Cre mice), and the corresponding jet-legged mouse model were used. Pgingivalis accelerates atherosclerosis progression by triggering arterial oxidative stress and inflammatory responses in ApoE-/- mice, accompanied by the perturbed circadian clock. Circadian clock disruption boosts P gingivalis-induced atherosclerosis progression. The mechanistic dissection shows that P gingivalis infection activates the TLRs-NF-κB signaling axis, which subsequently recruits DNMT-1 to methylate the BMAL1 promoter and thus suppresses BMAL1 transcription. The downregulation of BMAL1 releases CLOCK, which phosphorylates p65 and further enhances NF-κB signaling, elevating oxidative stress and inflammatory response in human aortic endothelial cells. Besides, the mouse model exhibits that joint administration of metronidazole and melatonin serves as an effective strategy for treating atherosclerotic cardiovascular diseases. CONCLUSIONS: P gingivalis accelerates atherosclerosis via the NF-κB-BMAL1-NF-κB signaling loop. Melatonin and metronidazole are promising auxiliary medications toward atherosclerotic cardiovascular diseases.

Circadian BMAL1 regulates mandibular condyle development by hedgehog pathway.

OBJECTIVE: Chondrogenesis and endochondral ossification in mandibular condyle play crucial roles in maxillofacial morphogenesis and function. Circadian regulator brain and muscle arnt-like 1 (BMAL1) is proven to be essential for embryonic and postnatal development. The goal of this study was to define the functions of BMAL1 in the embryonic and postnatal growth of mandibular condylar cartilages (MCC). MATERIALS AND METHODS: Micro-CT, TUNEL staining and EdU assay were performed using BMAL1-deficient mice model, and in vitro experiments were performed using rat chondrocytes isolated from MCC. RNA sequencing in mandibular condyle tissues from Bmal1-/- mice and the age-matched wild-type mice was used for transcriptional profiling at different postnatal stages. RESULTS: The expression levels of BMAL1 decrease gradually in MCC. BMAL1 is proved to regulate sequential chondrocyte differentiation, and its deficiency can result in the impairment of endochondral ossification of MCC. RNA sequencing reveals hedgehog signalling pathway is the potential target of BMAL1. BMAL1 regulates hedgehog signalling and affects its downstream cascades through directly binding to the promoters of Ptch1 and Ihh, modulating targets of hedgehog signalling which is indispensable for endochondral ossification. Importantly, the short stature phenotypes caused by BMAL1 deficiency can be rescued by hedgehog signalling activator. CONCLUSIONS: Collectively, these results indicate that BMAL1 plays critical roles on chondrogenesis and endochondral ossification of MCC, giving a new insight on potential therapeutic strategies for facial dysmorphism.

Periodic Oxaliplatin Administration in Synergy with PER2-Mediated PCNA Transcription Repression Promotes Chronochemotherapeutic Efficacy of OSCC.

Developing chemotherapeutic resistance affects clinical outcomes of oxaliplatin treatment on various types of cancer. Thus, it is imperative to explore alternative therapeutic strategies to improve the efficacy of oxaliplatin. Here, it is shown that circadian regulator period 2 (PER2) can potentiate the cytotoxicity of oxaliplatin and boost cell apoptosis by inhibiting DNA adducts repair in human oral squamous cell carcinoma (OSCC) cells. The circadian timing system is closely involved in controling the activity of DNA adducts repair and gives it a 24 h rhythm. The mechanistic dissection clarifies that PER2 can periodically suppress proliferating cell nuclear antigen (PCNA) transcription by pulling down circadian locomotor output cycles kaput-brain and muscle arnt-like 1 heterodimer from PCNA promoter in a CRY1/2-dependent manner, which subsequently impedes oxaliplatin-induced DNA adducts repair. Similarly, PER2 is capable of improving the efficacy of classical DNA-damaging chemotherapeutic agents. The tumor-bearing mouse model displays PER2 can be deployed as an oxaliplatin administration timing biomarker. In summary, it is believed that the chronochemotherapeutic strategy matching PER2 expression rhythm can efficiently improve the oxaliplatin efficacy of OSCC.

New Insights Into the Circadian Rhythm and Its Related Diseases.

Circadian rhythms (CR) are a series of endogenous autonomous oscillators generated by the molecular circadian clock which acting on coordinating internal time with the external environment in a 24-h daily cycle. The circadian clock system is a major regulatory factor for nearly all physiological activities and its disorder has severe consequences on human health. CR disruption is a common issue in modern society, and researches about people with jet lag or shift works have revealed that CR disruption can cause cognitive impairment, psychiatric illness, metabolic syndrome, dysplasia, and cancer. In this review, we summarized the synchronizers and the synchronization methods used in experimental research, and introduced CR monitoring and detection methods. Moreover, we evaluated conventional CR databases, and analyzed experiments that characterized the underlying causes of CR disorder. Finally, we further discussed the latest developments in understanding of CR disruption, and how it may be relevant to health and disease. Briefly, this review aimed to synthesize previous studies to aid in future studies of CR and CR-related diseases.

BMAL1 deficiency promotes skeletal mandibular hypoplasia via OPG downregulation.

OBJECTIVES: Skeletal mandibular hypoplasia (SMH), a common type of developmental deformities, results in impaired aesthetics of facial profile, occlusal dysfunction and poor life quality. In this study, BMAL1 deficiency leads to SMH formation, and we aim to investigate the mechanism by which BMAL1 deficiency induces SMH. MATERIALS AND METHODS: Circadian rhythm-disordered mouse models were constructed by placing animals in a jet lag schedule of 6-h light advance every 7 days for 4 or 8 weeks. The OPG expression was evaluated by histomorphometry, immunohistochemistry and western blot analysis. The mechanism by which BMAL1 affects OPG expression was investigated by chromatin immunoprecipitation and luciferase reporter assays. The phenotypes caused by BMAL1 knockout can be rescued by exogenous supplementation with OPG. RESULTS: We demonstrate that the expressions of BMAL1 and OPG decreased in SMH patients. Circadian rhythm-disordered mice and Bmal1-/- mice exhibited decreased expression of OPG, reduced bone mass and bone size of mandibles. Our results revealed that BMAL1 bound directly to the Opg promoter and upregulated its expression, thus inhibiting osteoclast differentiation. BMAL1 deficiency increased osteoclast differentiation by downregulating OPG expression. In vitro, the enhancement effect of osteoclast differentiation caused by BMAL1 knockdown was significantly reversed by exogenous supplementation with OPG. Importantly, bone loss caused by BMAL1 knockout can be partially reversed by injecting OPG Intraperitoneally. CONCLUSIONS: These results indicate that the circadian clock plays a critical role in the growth and development of mandible by regulating OPG expression, and present a potential therapeutic strategy to prevent SMH.

BMAL1 Deficiency Contributes to Mandibular Dysplasia by Upregulating MMP3.

Skeletal mandibular hypoplasia (SMH), one of the common types of craniofacial deformities, seriously affects appearance, chewing, pronunciation, and breathing. Moreover, SMH is prone to inducing obstructive sleep apnea syndrome. We found that brain and muscle ARNT-like 1 (BMAL1), the core component of the molecular circadian oscillator, was significantly decreased in mandibles of juvenile SMH patients. Accordingly, SMH was observed in circadian-rhythm-disrupted or BMAL1-deficient mice. RNA sequencing and protein chip analyses suggested that matrix metallopeptidase 3 (MMP3) is the potential target of BMAL1. Interestingly, in juvenile SMH patients, we observed that MMP3 was obviously increased. Consistently, MMP3 was upregulated during the whole growth period of 3-10 weeks in Bmal1-/- mice. Given these findings, we set out to characterize the underlying mechanism and found BMAL1 deficiency enhanced Mmp3 transcription through activating p65 phosphorylation. Together, our results provide insight into the mechanism by which BMAL1 is implicated in the pathogenesis of SMH.