Expert consensus on pediatric orthodontic therapies of malocclusions in children

Malocclusion,identified by the World Health Organization(WHO)as one of three major oral diseases,profoundly impacts the dental-maxillofacial functions,facial esthetics,and long-term development of~260 million children in China.Beyond its physical manifestations,malocclusion also significantly influences the psycho-social well-being of these children.Timely intervention in malocclusion can foster an environment conducive to dental-maxillofacial development and substantially decrease the incidence of malocclusion or reduce the severity and complexity of malocclusion in the permanent dentition,by mitigating the negative impact of abnormal environmental influences on the growth.Early orthodontic treatment encompasses accurate identification and treatment of dental and maxillofacial morphological and functional abnormalities during various stages of dental-maxillofacial development,ranging from fetal stages to the early permanent dentition phase.From an economic and societal standpoint,the urgency for effective early orthodontic treatments for malocclusions in childhood cannot be overstated,underlining its profound practical and social importance.This consensus paper discusses the characteristics and the detrimental effects of malocclusion in children,emphasizing critical need for early treatment.It elaborates on corresponding core principles and fundamental approaches in early orthodontics,proposing comprehensive guidance for preventive and interceptive orthodontic treatment,serving as a reference for clinicians engaged in early orthodontic treatment.

Autophagy in bone homeostasis and the onset of osteoporosis

Autophagy is an evolutionarily conserved intracellular process,in which domestic cellular components are selectively digested for the recycling of nutrients and energy.This process is indispensable for cell homeostasis maintenance and stress responses.Both genetic and functional studies have demonstrated that multiple proteins involved in autophagic activities are critical to the survival,differentiation,and functioning of bone cells,including osteoblasts,osteocytes,and osteoclasts.Dysregulation at the level of autophagic activity consequently disturbs the balance between bone formation and bone resorption and mediates the onset and progression of multiple bone diseases,including osteoporosis.This review aims to introduce the topic of autophagy,summarize the understanding of its relevance in bone physiology,and discuss its role in the onset of osteoporosis and therapeutic potential.

DNA N^6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs

ALKBH1 was recently discovered as a demethylase for DNA N6-methyladenine （N6-mA）, a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the role of ALKBH1 and DNA N6-mA in regulating osteogenic differentiation is largely unknown. In this study, we demonstrated that the expression of ALKBH1 in human mesenchymal stem cells （MSCs） was upregulated during osteogenic induction. Knockdown of ALKBH1 increased the genomic DNA N6-mA levels and significantly reduced the expression of osteogenic-related genes, alkaline phosphatase activity, and mineralization. ALKBHl-depleted MSCs also exhibited a restricted capacity for bone formation in vivo. By contrast, the ectopic overexpression of ALKBH1 enhanced osteoblastic differentiation. Mechanically, we found that the depletion of ALKBH1 resulted in the accumulation of N6-mA on the promoter region of ATF4, which subsequently silenced ATF4 transcription. In addition, restoring the expression of ATP by adenovirus-mediated transduction successfully rescued osteogenic differentiation. Taken together, our results demonstrate that ALKBH1 is indispensable for the osteogenic differentiation of MSCs and indicate that DNA N6-mA modifications area new mechanism for the epigenetic regulation of stem cell differentiation.

Parathyroid hormone increases alveolar bone homoeostasis during orthodontic tooth movement in rats with periodontitis via crosstalk between STAT3 and β-catenin

Periodontitis patients are at risk of alveolar bone loss during orthodontic treatment.The aim of this study was to investigate whether intermittent parathyroid hormone(1–34)treatment(iPTH)could reduce alveolar bone loss during orthodontic tooth movement(OTM)in individuals with periodontitis and the underlying mechanism.A rat model of OTM in the context of periodontitis was established and alveolar bone loss was observed.The control,iPTH and iPTH+stattic groups received injections of vehicle,PTH and vehicle,or PTH and the signal transducer and activator of transcription 3(STAT3)inhibitor stattic,respectively.iPTH prevented alveolar bone loss by enhancing osteogenesis and suppressing bone resorption in the alveolar bone during OTM in rats with periodontitis.This effect of iPTH was along with STAT3 activation and reduced by a local injection of stattic.iPTH promoted osteoblastic differentiation and might further regulate the Wnt/β-catenin pathway in a STAT3-dependent manner.The findings of this study suggest that iPTH might reduce alveolar bone loss during OTM in rats with periodontitis through STAT3/β-catenin crosstalk.

circ_0003204 regulates the osteogenic differentiation of human adipose-derived stem cells via miR-370-3p/HDAC4 axis

Human adipose-derived stem cells(hASCs)are a promising cell type for bone tissue regeneration.Circular RNAs(circRNAs)have been shown to play a critical role in regulating various cell differentiation and involve in mesenchymal stem cell osteogenesis.However,how circRNAs regulate hASCs in osteogenesis is still unclear.Herein,we found circ_0003204 was significantly downregulated during osteogenic differentiation of hASCs.Knockdown of circ_0003204 by si RNA or overexpression by lentivirus confirmed circ_0003204 could negatively regulate the osteogenic differentiation of hASCs.We performed dual-luciferase reporting assay and rescue experiments to verify circ_0003204 regulated osteogenic differentiation via sponging miR-370-3p.We predicted and confirmed that miR-370-3p had targets in the 3′-UTR of HDAC4 m RNA.The following rescue experiments indicated that circ_0003204 regulated the osteogenic differentiation of hASCs via miR-370-3p/HDAC4 axis.Subsequent in vivo experiments showed the silencing of circ_0003204 increased the bone formation and promoted the expression of osteogenic-related proteins in a mouse bone defect model,while overexpression of circ_0003204 inhibited bone defect repair.Our findings indicated that circ_0003204 might be a promising target to promote the efficacy of hASCs in repairing bone defects.

LITTIP/Lgr6/HnRNPK complex regulates cementogenesis via Wnt signaling

Orthodontically induced tooth root resorption(OIRR)is a serious complication during orthodontic treatment.Stimulating cementum repair is the fundamental approach for the treatment of OIRR.Parathyroid hormone(PTH)might be a potential therapeutic agent for OIRR,but its effects still lack direct evidence,and the underlying mechanisms remain unclear.This study aims to explore the potential involvement of long noncoding RNAs(lncRNAs)in mediating the anabolic effects of intermittent PTH and contributing to cementum repair,as identifying lncRNA-disease associations can provide valuable insights for disease diagnosis and treatment.Here,we showed that intermittent PTH regulates cell proliferation and mineralization in immortalized murine cementoblast OCCM-30 via the regulation of the Wnt pathway.In vivo,daily administration of PTH is sufficient to accelerate root regeneration by locally inhibiting Wnt/β-catenin signaling.Through RNA microarray analysis,lncRNA LITTIP(LGR6 intergenic transcript under intermittent PTH)is identified as a key regulator of cementogenesis under intermittent PTH.Chromatin isolation by RNA purification(ChIRP)and RNA immunoprecipitation(RIP)assays revealed that LITTIP binds to mRNA of leucine-rich repeatcontaining G-protein coupled receptor 6(LGR6)and heterogeneous nuclear ribonucleoprotein K(HnRNPK)protein.Further cotransfection experiments confirmed that LITTIP plays a structural role in the formation of the LITTIP/Lgr6/HnRNPK complex.Moreover,LITTIP is able to promote the expression of LGR6 via the RNA-binding protein HnRNPK.Collectively,our results indicate that the intermittent PTH administration accelerates root regeneration via inhibiting Wnt pathway.The lncRNA LITTIP is identified to negatively regulate cementogenesis,which activates Wnt/β-catenin signaling via high expression of LGR6 promoted by HnRNPK.

Lithium chloride promotes osteogenesis and suppresses apoptosis during orthodontic tooth movement in osteoporotic model via regulating autophagy

Osteoporosis is a widely distributed disease that may cause complications such as accelerated tooth movement,bone resorption,and tooth loss during orthodontic treatment.Promoting bone formation and reducing bone resorption are strategies for controlling these complications.For several decades,the autophagy inducer lithium chloride(LiCl)has been explored for bipolar.In this study,we investigated the autophagy-promoting effect of LiCl on bone remodeling under osteoporotic conditions during tooth movement.Ovariectomy was used to induce osteoporosis status in vivo.The results showed that LiCl rejuvenated autophagy,decreased apoptosis,and promoted bone formation,thus protecting tooth movement in osteoporotic mice.Furthermore,in vitro experiments showed that LiCl reversed the effects of ovariectomy on bone marrow-derived mesenchymal stem cells(BMSCs)extracted from ovariectomized mice,promoting osteogenesis and suppressing apoptosis by positively regulating autophagy.These findings suggest that LiCl can significantly decrease adverse effects of osteoporosis on bone remodeling,and that it has great potential significance in the field of bone formation during tooth movement in osteoporosis patients.

Hydrogel platform with tunable stiffness based on magnetic nanoparticles cross-linked GelMA for cartilage regeneration and its intrinsic biomechanism

Cartilage injury affects numerous individuals,but the efficient repair of damaged cartilage is still a problem in clinic.Hydrogel is a potent scaffold candidate for tissue regeneration,but it remains a big challenge to improve its mechanical property and figure out the interaction of chondrocytes and stiffness.Herein,a novel hybrid hydrogel with tunable stiffness was fabricated based on methacrylated gelatin(GelMA)and iron oxide nanoparticles(Fe_(2)O_(3))through chemical bonding.The stiffness of Fe_(2)O_(3)/GelMA hybrid hydrogel was controlled by adjusting the concentration of magnetic nanoparticles.The hydrogel platform with tunable stiffness modulated its cellular properties including cell morphology,microfilaments and Young’s modulus of chondrocytes.Interestingly,Fe_(2)O_(3)/GelMA hybrid hydrogel promoted oxidative phosphorylation of mitochondria and facilitated catabolism of lipids in chondrocytes.As a result,more ATP and metabolic materials generated for cellular physiological activities and organelle component replacements in hybrid hydrogel group compared to pure GelMA hydrogel.Furthermore,implantation of Fe_(2)O_(3)/GelMA hybrid hydrogel in the cartilage defect rat model verified its remodeling potential.This study provides a deep understanding of the bio-mechanism of Fe_(2)O_(3)/GelMA hybrid hydrogel interaction with chondrocytes and indicates the hydrogel platform for further application in tissue engineering.