Evaluation of modified clear Twin Block aligner in treating adolescents with skeletal class II malocclusion: A two-centre cephalometric study.

INTRODUCTION: The purpose of this study was to evaluate the therapeutic effect of modified clear Twin Block (CTB) aligner and traditional twin block (TB) appliance from skeletal, dentoalveolar and soft tissue changes in adolescents with skeletal class II malocclusion. METHODS: A total of 80 adolescents, included in this study from two medical centres, were distributed into CTB group, TB group and control group based on the treatment they received. Lateral cephalograms at pre-treatment (T1) and post-treatment (T2) were measured by modified Pancherz's cephalometric analysis, and dentoskeletal and soft tissue changes were analysed by independent-sample t-test, paired-sample t-test, ANOVA test and Scheffe's Post Hoc test. RESULTS: Seventy-five adolescents completed the study, including 32 in the CTB group, 32 in the TB group and 11 in the control group. Both CTB and TB treatment showed significant differences in most dentoskeletal and soft tissue measurements. Compared with the control group, improvements were observed in class II molar relationship through significant different in S Vert/Ms-S Vert/Mi in the CTB group (P < .01) and the TB group (P < .001), as well as deep overjet through significant different in S Vert/Is-S Vert/Ii in the CTB group (P < .001) and the TB group (P < .001). Besides, the CTB group also showed less protrusion of lower incisors and resulted in a more significant improvement in profile with fewer adverse effects on speaking, eating and social activities. CONCLUSIONS: For adolescents with skeletal class II malocclusion, CTB appliance was as effective as TB on improving dentoskeletal and soft tissue measurements, featuring more reliable teeth control and patient acceptance.

ScRNA-seq links dental fibroblasts heterogeneity with mechanoresponsiveness.

BACKGROUND AND OBJECTIVE: Periodontal ligament (PDL) and dental pulp (DP) share a common origin but have distinct biological and mechanical functions. To what extent the mechanoresponsive property of PDL can be attributed to its unique transcriptional profiles of cellular heterogeneity is unclear. This study aims to decipher cellular heterogeneity and distinct mechanoresponsive characteristics of odontogenic soft tissues and their underlying molecular mechanisms. MATERIALS AND METHODS: A single-cell comparison of digested human periodontal ligament (PDL) and dental pulp (DP) was performed using scRNA-seq. An in vitro loading model was constructed to measure mechanoresponsive ability. Dual-luciferase assay, overexpression, and shRNA knockdown were used to investigate the molecular mechanism. RESULTS: Our results demonstrate striking fibroblast heterogeneity across and within human PDL and DP. We demonstrated that a tissue-specific subset of fibroblasts existed in PDL exhibiting high expression of mechanoresponsive extracellular matrix (ECM) genes, which was verified by an in vitro loading model. ScRNA-seq analysis indicated a particularly enriched regulator in PDL-specific fibroblast subtype, Jun Dimerization Protein 2 (JDP2). Overexpression and knockdown of JDP2 extensively regulated the downstream mechanoresponsive ECM genes in human PDL cells. The force loading model demonstrated that JDP2 responded to tension and that knockdown of JDP2 effectively inhibited the mechanical force-induced ECM remodeling. CONCLUSIONS: Our study constructed the PDL and DP ScRNA-seq atlas to demonstrate PDL and DP fibroblast cellular heterogeneity and identify a PDL-specific mechanoresponsive fibroblast subtype and its underlying mechanism.

Camouflage orthodontic treatment combined with genioplasty distraction osteogenesis for skeletal class II relationship secondary to osteosarcoma excision surgery.

OBJECTIVE: The treatment of orthodontic patients who survive head and neck tumors is challenging because of dentoskeletal deformities and other unexpected dental and facial complications. This case report describes the case of a 26-year-old woman who presented with mandibular retrognathia after survival from osteosarcoma. CLINICAL CONSIDERATIONS: Camouflage orthodontic treatment was chosen instead of combined orthodontic-orthognathic surgery after primary reconstructive surgery with an iliac bone graft. Genioplasty distraction osteogenesis (DO) was performed to achieve an optimal facial profile. Although unexpected condyle dislocation and epithelial hyperplasia occurred during treatment, a favorable facial profile and optimal skeletal and dental relationships were accomplished after 32 months of treatment. CONCLUSIONS: The patient underwent genioplasty DO and experienced unexpected left condyle dislocation. However, the treatment achieved esthetic goals after intermaxillary elastics were applied.

STAT3 controls osteoclast differentiation and bone homeostasis by regulating NFATc1 transcription.

The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a central role in cell survival and function. STAT3 has been demonstrated to participate in the maintenance of bone homeostasis in osteoblasts, but its role in osteoclasts in vivo remains poorly defined. Here, we generated a conditional knockout mouse model in which Stat3 was deleted in osteoclasts using a cathepsin K-Cre (Ctsk-Cre) driver. We observed that osteoclast-specific Stat3 deficiency caused increased bone mass in mice, which we attributed to impaired bone catabolism by osteoclasts. Stat3-deficient bone marrow macrophages (BMMs) showed decreased expression of nuclear factor of activated T cells, cytoplasm 1 (NFATc1), and reduced osteoclast differentiation determined by decreases in osteoclast number, tartrate-resistant acid phosphatase activity, and expression of osteoclast marker genes. Enforced expression of NFATc1 in Stat3-deficient BMMs rescued the impaired osteoclast differentiation. Mechanistically, we revealed that STAT3 could drive the transcription of NFATc1 by binding to its promoter. Furthermore, preventing STAT3 activation by using an inhibitor of upstream phosphorylases, AG490, also impaired osteoclast differentiation and formation in a similar way as gene deletion of Stat3 In summary, our data provide the first evidence that STAT3 is significant in osteoclast differentiation and bone homeostasis in vivo, and it may be identified as a potential pharmacological target for the treatment of bone metabolic diseases through regulation of osteoclast activity.

Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice.

Mammalian target of rapamycin complex 1 (mTORC1) is involved in anabolic metabolism in both osteoblasts and chondrocytes, but the role of mTORC1 in osteoclast biology in vivo remains to be elucidated. In this study, we showed that deletion of regulatory-associated protein of mTOR (Raptor) in osteoclasts led to an increase in bone mass with decreased bone resorption. Raptor-deficient bone marrow-derived macrophages exhibited lower mTORC1-S6K1 signaling and retarded osteoclast differentiation, as determined by the number of osteoclasts, tartrate-resistant acid phosphatase activity, and expression of osteoclast-specific genes. Enforced expression of constitutively active S6K1 rescued the impaired osteoclast differentiation in Raptor-deficient bone marrow-derived macrophages. Furthermore, pharmacological inhibition of mTORC1 signaling by rapamycin could also inhibit osteoclast differentiation and osteoclast-specific gene expression. Taken together, our findings demonstrate that mTORC1 plays a key role in the network of catabolic bone resorption in osteoclasts and may serve as a potential pharmacological target for the regulation of osteoclast activity in bone metabolic disorders.

The Specific Morphological Features of Alveolar Bone.

OBJECTIVE: The aim of the study was to study the specific morphological features of alveolar bone and compare it to femoral bone in rats. METHODS: Twelve 3-month-old nonpregnant female Sprague-Dawley rats were used in the present study. The left maxillae and femurs of 6 rats were used for micro-computed tomography (micro-CT) scanning. The trabecular bone of the distal femur and the interradicular alveolar bone of the maxillary first molar were reconstructed and analyzed. Another 6 rats were used for histological analysis of trabecular bone and alveolar bone. RESULTS: Micro-CT analysis suggested that the femoral trabecular bone was porous with rod-like trabeculae with a scattered distribution in bone marrow, whereas alveolar bone showed a compact structure with plate-like trabeculae and limited bone marrow. Tissue mineral density, bone mineral density, bone volume fraction, and trabecular thickness were dramatically higher in the alveolar bone compared with that in the trabecular bone. Alveolar bone displayed lower trabecular number and trabecular separation. Histomorphometric analysis showed that alveolar bone was formed of compact bone with wide trabeculae, whereas femurs were composed of loose bone with finer trabeculae. CONCLUSIONS: In comparison to the spongiosa of the distal femur, alveolar bone displays specific morphological features with compact, wide, and highly mineralized trabeculae.

Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.

Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation in accumulated senescent cells (SnCs) with aging is essential for tissue homeostasis, and adequate ATP is important in cell activation for aged tissue repair. Strategies for ATP metabolism intervention hold prospects for therapeutic advances. Here, we found energy metabolic changes in aging skin from patients and mice. Our data show that metformin engineered EV (Met-EV) can enhance aged mouse skin repair, as well as ameliorate cellular senescence and restore cell dysfunctions. Notably, ATP metabolism was remodeled as reduced glycolysis and enhanced OXPHOS after Met-EV treatment. We show Met-EV rescue senescence-induced mitochondria dysfunctions and mitophagy suppressions, indicating the role of Met-EV in remodeling mitochondrial functions via mitophagy for adequate ATP production in aged tissue repair. Our results reveal the mechanism for SnCs rejuvenation by EV and suggest the disturbed energy metabolism, essential in age-related defects, to be a potential therapeutic target for facilitating aged tissue repair.

Occlusal force orchestrates alveolar bone homeostasis via Piezo1 in female mice.

Healthy alveolar bone is the cornerstone of oral function and oral treatment. Alveolar bone is highly dynamic during the entire lifespan and is affected by both systemic and local factors. Importantly, alveolar bone is subjected to unique occlusal force in daily life, and mechanical force is a powerful trigger of bone remodeling, but the effect of occlusal force in maintaining alveolar bone mass remains ambiguous. In this study, the Piezo1 channel is identified as an occlusal force sensor. Activation of Piezo1 rescues alveolar bone loss caused by a loss of occlusal force. Moreover, we identify Piezo1 as the mediator of occlusal force in osteoblasts, maintaining alveolar bone homeostasis by directly promoting osteogenesis and by sequentially regulating catabolic metabolism through Fas ligand (FasL)-induced osteoclastic apoptosis. Interestingly, Piezo1 activation also exhibits remarkable efficacy in the treatment of alveolar bone osteoporosis caused by estrogen deficiency, which is highly prevalent among middle-aged and elderly women. Promisingly, Piezo1 may serve not only as a treatment target for occlusal force loss-induced alveolar bone loss but also as a potential target for metabolic bone loss, especially in older patients.

Daily occlusal force and estrogen synergistically maintain alveolar bone homeostasis. PIEZO1 in osteoblasts plays a critical role in sensing occlusal force and maintaining bone mass. PIEZO1 may promote osteoclastic apoptosis through osteoblast-secreted FasL through a PIEZO1-STAT3/ESR1-FasL pathway. Restoration of occlusal force with dental therapies as early as possible to prevent alveolar bone loss is the major priority in oral health care. PIEZO1 may serve as a potential target for bone metabolism disorders.

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.

p38-MAPK signaling pathway is not involved in osteogenic differentiation during early response of mesenchymal stem cells to continuous mechanical strain.

Mechanical stimuli play a significant role in the regulation of bone remodeling during orthodontic tooth movement. However, the correlation between mechanical strain and bone remodeling is still poorly understood. In this study, we used a model of continuous mechanical strain (CMS) on bone mesenchymal stem cells (BMSCs) to investigate the proliferation and osteogenic differentiation of BMSCs and the mechanism of mechano-transduction. A CMS of 10 % at 1 Hz suppressed the proliferation of BMSCs and induced early osteogenic differentiation within 48 h by activating Runx2 and increasing alkaline phosphatase (ALP) activity and mRNA expression of osteogenesis-related genes (ALP, collagen type I, and osteopontin). Regarding mitogen-activated protein kinase (MAPK) activation, CMS induced phased phosphorylation of p38 consisting of a rapid induction of p38 MAPK at 10 min and a rapid decay after 1 h. Furthermore, the potent p38 inhibitor SB203580 blocked the induction of p38 MAPK signaling, but had little effect on subsequent osteogenic events. These results demonstrate that mechanical strain may act as a stimulator to induce the differentiation of BMSCs into osteoblasts, which is a vital function for bone formation in orthodontic tooth movement. However, activation of the p38 signaling pathway may not be involved in this process.

Effect of mechanical stretch on the proliferation and differentiation of BMSCs from ovariectomized rats.

Osteoporosis is characterized by a broken balance between bone formation and bone resorption. Mechanical stress has been considered to be an important factor in bone modeling and remodeling. However, biological responses of stromal cells in osteoporosis to mechanical stimuli remain unknown. To explore the correlation between mechanical stress and osteoblastic differentiation of bone mesenchymal stem cells (BMSCs) in osteoporosis, we built an osteoporosis model in ovariectomized (OVX) rats, and then investigated proliferation, alkaline phosphatase (ALP) activity, and the expression of osteoblastic genes in BMSCs under mechanical stress of 5 and 10% elongation, using the Flexercell Strain system. The proliferation of BMSCs was detected using alamarBlue. The expression of osteoblastic genes was analyzed by real-time quantitative polymerase chain reaction. Protein expression was examined by Western blotting. BMSCs (OVX) and BMSCs (Sham-operated, Sham in short) proliferations were inhibited at 5 and 10% elongation at day 3, compared with the un-stretched group, while BMSCs (OVX) proliferation was slower than BMSCs (Sham). ALP activity increased significantly at 10% elongation in both cells, but it was less active in BMSCs (OVX) than BMSCs (Sham). At days 3 and 7, the mRNA expression of osteoblastic genes was unregulated by mechanical stretch (5 and 10 % elongation); however, osteoblastic gene expression in BMSCs (OVX) was less than that in BMSCs (Sham). The mRNA and protein expression of Runx2 showed similar trends in BMSCs (OVX) under mechanical stretch. These results indicate that the mechanical stretch stimulates osteoblastic differentiation of BMSCs (OVX); however, this differentiation was weaker than that of BMSCs (Sham).

Temporomandibular joint changes after activator appliance therapy: a prospective magnetic resonance imaging study.

The aim of this prospective clinical and magnetic resonance imaging study was to analyze the effect of 1-year Activator (Yi-fan Dental Co., Shanghai, China) treatment in internal anatomical relationships of the temporomandibular joint (TMJ) complex, including the condyle-disc relationship, condyle-fossa relationship, condylar height change, disc length change, and morphologic change of the glenoid fossa. The study was composed of patients with class II division 1 malocclusion (11 girls and 13 boys) who underwent 1-year Activator treatment. All the patients were in the acceleration or peak phase of the pubertal growth spurt. Magnetic resonance imaging in closed-mouth position and lateral cephalometric radiographs before and after 1 year of Activator treatment were analyzed metrically. Overall, condylar height showed a significant increase (P < 0.001), and the eminence angle decreased (P = 0.037). TMJ disc length has no statistically significant change before and after treatment. A slight advancement (P = 0.041) was found in the sagittal condylar position. A significant backward movement (P = 0.04) was shown in the sagittal disc position. Our results showed that the disc is not impaired by Activator therapy; it seems possible that adaptive remodeling, including a shallower glenoid fossa and increased condylar height, was seen after treatment.

Three-dimensional analysis of soft tissue changes in full-face view after surgical correction of skeletal class III malocclusion.

OBJECTIVE: The objective of this study was to evaluate changes in soft tissue in full-face view because of surgical correction of skeletal Class III malocclusion, using 3-dimensional (3D) laser scanning. METHODS: Twenty-seven subjects with skeletal Class III malocclusion [11 males; mean age (SD), 24.0 (5.7) years] underwent bilateral sagittal split ramus osteotomy for mandibular setback combined with Lefort I osteotomy with/without maxillary advancement. Twelve patients (group 1) had mandibular setback surgery, and the other 15 (group 2) had combination surgery. Lateral cephalograms and 3D facial scan images were assessed preoperatively and postoperatively. The facial widths upon superimposition of 3D facial images were measured in the same coordinates using a Rapidform 2006 system. Paired and independent t tests were done for statistical analysis. RESULTS: The midface soft tissue broadened significantly above the cheilion plane postoperatively (P < 0.05). A larger change was observed nearer to subnasale plane, and a similar trend was seen among the horizontal planes in 1- or 2-jaw surgery groups. The widths from the exocanthion plane to the subnasale plane increased more in group 2 [mean (SD), 4.45 (2.45) mm, 8.71 (2.92) mm, and 7.62 (3.13) mm] than those in group 1 [mean (SD), 1.26 (0.97) mm, 1.84 (1.06) mm, and 1.35 (0.65) mm], and this difference was significant (P < 0.05). There was a decrease below the cheilion plane with mandibular setback between groups, but this difference was not significant. CONCLUSIONS: The measurement method used here for the shape outline of the lateral parts of the face could provide quantitative data for the clinical evaluation and objective analysis of the human face in full-face view. The midface soft tissue in subjects with skeletal Class III malocclusion exhibited a greater increase in width after bimaxillary surgery procedures than mandibular setback-only surgery.

Surgical Management for Vertical Maxillary Excess.

Orthognathic surgery is an effective approach to correct vertical maxillary excess (VME), which is a common maxillofacial deformity and exhibits excessive vertical development of maxilla. This review summarizes different clinical features of total, anterior and posterior VME, as well as corresponding surgical managements guided by preoperative computer-assisted surgical planning. The virtual simulation will do favor to the final determination of individual surgical plans to achieve satisfactory outcomes. Finally, a typical clinical case will be presented to demonstrate the surgical management of VME.

Osteoblastic STAT3 Is Crucial for Orthodontic Force Driving Alveolar Bone Remodeling and Tooth Movement.

Mechanical force is essential to shape the internal architecture and external form of the skeleton by regulating the bone remodeling process. However, the underlying mechanism of how the bone responds to mechanical force remains elusive. Here, we generated both orthodontic tooth movement (OTM) model in vivo and a cyclic stretch-loading model in vitro to investigate biomechanical regulation of the alveolar bone. In this study, signal transducer and activator of transcription 3 (STAT3) was screened as one of the mechanosensitive proteins by protein array analysis of cyclic stretch-loaded bone mesenchymal stem cells (BMSCs) and was also proven to be activated in osteoblasts in response to the mechanical force during OTM. With an inducible osteoblast linage-specific Stat3 knockout model, we found that Stat3 deletion decelerated the OTM rate and reduced orthodontic force-induced bone remodeling, as indicated by both decreased bone resorption and formation. Both genetic deletion and pharmacological inhibition of STAT3 in BMSCs directly inhibited mechanical force-induced osteoblast differentiation and impaired osteoclast formation via osteoblast-osteoclast cross-talk under mechanical force loading. According to RNA-seq analysis of Stat3-deleted BMSCs under mechanical force, matrix metalloproteinase 3 (Mmp3) was screened and predicted to be a downstream target of STAT3. The luciferase and ChIP assays identified that Stat3 could bind to the Mmp3 promotor and upregulate its transcription activity. Furthermore, STAT3-inhibitor decelerated tooth movement through inhibition of the bone resorption activity, as well as MMP3 expression. In summary, our study identified the mechanosensitive characteristics of STAT3 in osteoblasts and highlighted its critical role in force-induced bone remodeling during orthodontic tooth movement via osteoblast-osteoclast cross-talk. © 2022 American Society for Bone and Mineral Research (ASBMR).

Exercise maintains bone homeostasis by promoting osteogenesis through STAT3.

Bone exhibits changes in density, strength, and microarchitecture in relation to mechanical loading mediated by exercise. Appropriate exercise maintains bone homeostasis, while the absence of exercise leads to disuse bone loss. However, the acting mechanism of mechanotransduction in bone remains unclear. We performed the running-wheel exercise and tail suspension model to study the effects of exercise on bone metabolism, and found that osteoblastic Signal transducer and activator of transcription 3 (STAT3) activity was closely related to exercise-induced bone mass and metabolism changes. With the Flexcell tension-loading system in vitro, mechanical force promoted STAT3 activity, which was accompanied by increased osteoblastic differentiation of the bone marrow mesenchymal stem cells (BMSCs). In contrast, the inhibition of STAT3 phosphorylation blocked force-induced osteoblastic differentiation. Furthermore, pharmacological inactivation of STAT3 impaired the increase in exercise-induced bone mass and osteogenesis. With an inducible conditional deletion mouse model, we found that the osteoblast lineage-specific Stat3 deletion could also block force-induced osteoblastic differentiation in vitro and impair exercise-promoted bone mass and osteogenesis in vivo. This confirmed the crucial role of osteoblastic STAT3 in exercise-mediated bone metabolism. Finally, colivelin, a STAT3 agonist, promoted osteoblastic differentiation in vitro and partly rescued exercise loss-induced disuse bone loss by improving osteogenesis in the tail suspension model. Taken together, our study revealed the essential role of STAT3 in maintaining exercise-mediated bone homeostasis. In addition, STAT3 might act as a potential target for osteoporosis caused by exercise loss.

Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers.

Stem cell-independent reprogramming of differentiated cells has recently been identified as an important paradigm for repairing injured tissues. Following periportal injury, mature hepatocytes re-activate reprogramming/progenitor-related genes (RRGs) and dedifferentiate into liver progenitor-like cells (LPLCs) in both mice and humans, which contribute remarkably to regeneration. However, it remains unknown which and how external factors trigger hepatocyte reprogramming. Here, by employing single-cell transcriptional profiling and lineage-specific deletion tools, we uncovered that periportal-specific LPLC formation was initiated by regionally activated Kupffer cells but not peripheral monocyte-derived macrophages. Unexpectedly, using in vivo screening, the proinflammatory factor IL-6 was identified as the niche signal repurposed for RRG induction via STAT3 activation, which drove RRG expression through binding to their pre-accessible enhancers. Notably, RRGs were activated through injury-specific rather than liver embryogenesis-related enhancers. Collectively, these findings depict an injury-specific niche signal and the inflammation-mediated transcription in driving the conversion of hepatocytes into a progenitor phenotype.

Using Inducible Osteoblastic Lineage-Specific Stat3 Knockout Mice to Study Alveolar Bone Remodeling During Orthodontic Tooth Movement.

The alveolar bone, with a high turnover rate, is the most actively-remodeling bone in the body. Orthodontic tooth movement (OTM) is a common artificial process of alveolar bone remodeling in response to mechanical force, but the underlying mechanism remains elusive. Previous studies have been unable to reveal the precise mechanism of bone remodeling in any time and space due to animal model-related restrictions. The signal transducer and activator of transcription 3 (STAT3) is important in bone metabolism, but its role in osteoblasts during OTM is unclear. To provide in vivo evidence that STAT3 participates in OTM at specific time points and in particular cells during OTM, we generated a tamoxifen-inducible osteoblast lineage-specific Stat3 knockout mouse model, applied orthodontic force, and analyzed the alveolar bone phenotype. Micro-computed tomography (Micro-CT) and stereo microscopy were used to access OTM distance. Histological analysis selected the area located within three roots of the first molar (M1) in the cross-section of the maxillary bone as the region of interest (ROI) to evaluate the metabolic activity of osteoblasts and osteoclasts, indicating the effect of orthodontic force on alveolar bone. In short, we provide a protocol for using inducible osteoblast lineage-specific Stat3 knockout mice to study bone remodeling under orthodontic force and describe methods for analyzing alveolar bone remodeling during OTM, thus shedding new light on skeletal mechanical biology.

Early-Responsive Immunoregulation Therapy Improved Microenvironment for Bone Regeneration Via Engineered Extracellular Vesicles.

Overactivated inflammatory reactions hinder the bone regeneration process. Timely transformation of microenvironment from pro-inflammatory to anti-inflammatory after acute immune response is favorable for osteogenesis. Macrophages play an important role in the immune response to inflammation. Therefore, this study adopts TIM3 high expression extracellular vesicles (EVs) with immunosuppressive function to reshape the early immune microenvironment of bone injury, mainly by targeting macrophages. These EVs can be phagocytosed by macrophages, thereby increasing the infiltration of TIM3-positive macrophages (TIM3+ macrophages) and M2 subtypes. The TIM3+ macrophage group has some characteristics of M2 macrophages and secretes cytokines, such as IL-10 and TGF-ß1 to regulate inflammation. TIM3, which is highly expressed in the engineered EVs, mediates the release of anti-inflammatory cytokines by inhibiting the p38/MAPK pathway and promotes osseointegration by activating the Bmp2 promoter to enhance macrophage BMP2 secretion. After evenly loading the engineered EVs into the hydrogel, the continuous and slow release of EVsTIM3OE recruits more anti-inflammatory macrophages during the early stages of bone defect repair, regulating the immune microenvironment and eliminating the adverse effects of excessive inflammation. In summary, this study provides a new strategy for the treatment of refractory wounds through early inflammation control.

The odontoblastic differentiation of dental mesenchymal stem cells: molecular regulation mechanism and related genetic syndromes.

Dental mesenchymal stem cells (DMSCs) are multipotent progenitor cells that can differentiate into multiple lineages including odontoblasts, osteoblasts, chondrocytes, neural cells, myocytes, cardiomyocytes, adipocytes, endothelial cells, melanocytes, and hepatocytes. Odontoblastic differentiation of DMSCs is pivotal in dentinogenesis, a delicate and dynamic process regulated at the molecular level by signaling pathways, transcription factors, and posttranscriptional and epigenetic regulation. Mutations or dysregulation of related genes may contribute to genetic diseases with dentin defects caused by impaired odontoblastic differentiation, including tricho-dento-osseous (TDO) syndrome, X-linked hypophosphatemic rickets (XLH), Raine syndrome (RS), hypophosphatasia (HPP), Schimke immuno-osseous dysplasia (SIOD), and Elsahy-Waters syndrome (EWS). Herein, recent progress in the molecular regulation of the odontoblastic differentiation of DMSCs is summarized. In addition, genetic syndromes associated with disorders of odontoblastic differentiation of DMSCs are discussed. An improved understanding of the molecular regulation and related genetic syndromes may help clinicians better understand the etiology and pathogenesis of dentin lesions in systematic diseases and identify novel treatment targets.