a-3-d-visualization-technique-for-bone-remodeling-suture-expansion

A 3-D Visualization Technique for Bone Remodeling in a Suture Expansion Mouse Model

Craniofacial sutures play a crucial role beyond being fibrous joints connecting craniofacial bones; they also serve as the primary niche for calvarial and ...

Shanghai Jiao Tong University School of Medicine

Shanghai Jiao Tong University

Cleft palate, a common global congenital malformation, occurs due to disturbances in palatal growth, elevation, contact, and fusion during palatogenesis. The  () mutation has been discovered in humans with cleft lip and palate.  is expressed in both the epithelium and mesenchyme, with temporospatial diversity during palatogenesis. However, the specific role of  in palatogenesis has not been extensively discussed. Herein, we used  mice to generate an  mouse model (with an  exon 2 deletion) that exhibited a craniofacial syndrome involving a cleft palate and deficient mandibular size with 100% penetrance. A smaller palatal shelf size, delayed palatal elevation, and contact failure were investigated to be the intrinsic causes for cleft palate. Hyaluronic acid accumulation in the extracellular matrix (ECM) sharply decreased, while the cell density correspondingly increased in  mice. Additionally, significant decreases in cell proliferation were discovered in not only the palatal epithelium and mesenchyme but also among cells in Meckel's cartilage and around the mandibular bone in  mice. Serial sections of embryonic heads dissected at embryonic day 14.5 (E14.5) were subjected to craniofacial morphometric measurement. This highlighted the reduced oral volume owing to abnormal tongue size and descent, and insufficient mandibular size, which disturbed palatal elevation in  mice. These results indicate that  facilitates palatal growth and timely elevation by regulating cell proliferation and hyaluronic acid accumulation. Moreover,  ensures that the palatal elevation process has adequate space by influencing tongue descent, tongue morphology, and mandibular growth.

 Participates in Palatogenesis by Promoting Palatal Growth and Elevation.

The Advanced Mandibular Spring (AMS) was newly developed as a dentofacial orthopedic appliance in conjunctive use of clear aligners to treat Class II malocclusion with mandibular retrognathia in adolescents. This study aimed to launch a biomechanical assessment and evaluate whether the stress patterns generated by AMS promote mandibular growth.

Effects of the advanced mandibular spring on mandibular retrognathia treatment: a three-dimensional finite element study.

Osteoarthritis (OA) is a prevalent joint disease with no effective treatment strategies. Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis. Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies, the epigenetic control of OA remains unclear. Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. However, the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown. In this work, we confirmed the upregulation of JMJD3 in aberrant force-induced cartilage injury in vitro and in vivo. Functionally, inhibition of JMJD3 by its inhibitor, GSK-J4, or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury. Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model, and the therapeutic effect of GSK-J4 was validated. More importantly, we adopted a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was remarkably mitigated. Taken together, our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression. Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-siRNA nanocomplexes.

Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1.

 mutation was found in cleft palate patients. Our previous study indicated that  promotes timely elevation of palate by regulating hyaluronic acid (HA) accumulation at embryonic day 13.5 (E13.5). HA is synthesized by hyaluronic acid synthases (HAS) isoforms 1, 2, or 3. However, how FGF9 regulates HA in palatogenesis is still unclear.

FGF9 Promotes Expression of HAS2 in Palatal Elevation via the Wnt/β-Catenin/TCF7L2 Pathway.

The identification of predictive markers to determine the triggering phase prior to the onset of osteoporosis is essential to mitigate further irrevocable deterioration. To determine the early warning signs before osteoporosis, we used the dynamic network biomarker (DNB) approach to analyze time-series gene expression data in a zebrafish osteoporosis model, which revealed that cyclin-dependent kinase inhibitor 1 A (cdkn1a) is a core DNB. We found that cdkn1a negatively regulates osteogenesis, as evidenced by loss-of-function and gain-of-function studies. Specifically, CRISPR/Cas9-mediated cdkn1a knockout in zebrafish significantly altered skeletal development and increased bone mineralization, whereas inducible cdkn1a expression significantly contributed to osteoclast differentiation. We also found several mechanistic clues that cdkn1a participates in osteoclast differentiation by regulating its upstream signaling cascades. To summarize, in this study, we provided new insights into the dynamic nature of osteoporosis and identified cdkn1a as an early-warning signal of osteoporosis onset.

Dynamic network biomarker identifies cdkn1a-mediated bone mineralization in the triggering phase of osteoporosis.

During the intrusion of lower incisors with clear aligners (CAs), root disengagement from the alveolar bone often occurs, resulting in serious complications. This study aimed to determine the potential force mechanism of the mandibular anterior teeth under the pressure of CA, providing theoretical data for clinical practice.

Stress and movement trend of lower incisors with different IMPA intruded by clear aligner: a three-dimensional finite element analysis.

This study aimed to evaluate the zygomaticotemporal suture (ZTS) maturation, analyze the age distribution patterns of ZTS maturation stages, and investigate the relationship between ZTS and cervical vertebral maturation (CVM).

Zygomaticotemporal suture maturation evaluation in Chinese population using cone-beam computed tomography images.

Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less reactive oxygen species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE.

Article	Year
Participates in Palatogenesis by Promoting Palatal Growth and Elevation. Frontiers in physiology\| PubMed ID: 33959039	2021
Effects of the advanced mandibular spring on mandibular retrognathia treatment: a three-dimensional finite element study. BMC oral health\| PubMed ID: 35790937	2022
Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1. International journal of oral science\| PubMed ID: 35831280	2022
FGF9 Promotes Expression of HAS2 in Palatal Elevation via the Wnt/β-Catenin/TCF7L2 Pathway. Biomolecules\| PubMed ID: 36358989	2022
Dynamic network biomarker identifies cdkn1a-mediated bone mineralization in the triggering phase of osteoporosis. Experimental & molecular medicine\| PubMed ID: 36599933	2023
Stress and movement trend of lower incisors with different IMPA intruded by clear aligner: a three-dimensional finite element analysis. Progress in orthodontics\| PubMed ID: 36775824	2023
Zygomaticotemporal suture maturation evaluation in Chinese population using cone-beam computed tomography images. Korean journal of orthodontics\| PubMed ID: 37357423	2023
Matrix mechanics regulate the polarization state of bone marrow-derived neutrophils through the JAK1/STAT3 signaling pathway. Acta biomaterialia\| PubMed ID: 37467837	2023

Ruomei Li

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