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Osteocytes are the main sensitive cells in bone remodeling due to their potent functional cell processes from the mineralized bone matrix to the bone surface and the bone marrow. Neighboring osteocytes communicate with each other by these cell processes to achieve molecular exchange through gap junction channels. Platelet-derived growth factor-AA (PDGF-AA) has been reported to enhance bone tissue remodeling by promoting cell proliferation, migration, and autocrine secretion in osteoid cell linage. However, the effect of PDGF-AA on intercellular communication between osteocytes is still unclear. In the present study, we elucidated that PDGF-AA could enhance the formation of dendritic processes of osteocytes and the gap junctional intercellular communication by promoting the expression of connexin43 (Cx43). This modulation process was mainly dependent on the activation of phosphorylation of Akt protein by phosphatidylinositol 3-kinase (PI3K)/Akt (also known as protein kinase B, PKB) signaling. Inhibition of PI3K/Akt signaling decreased the Cx43 expression induced by PDGF-AA. These results establish a bridge between PDGF-AA and cell-cell communication in osteocytes, which could help us understand the molecular exchange between bone cells and fracture healing.

Although several genome‐wide association studies (GWAS) of non‐syndromic cleft lip with or without cleft palate (NSCL/P) have been reported, more novel association signals are remained to be exploited. Here, we performed an in‐depth analysis of our previously published Chinese GWAS cohort study with replication in an extra dbGaP case‐parent trios and another in‐house Nanjing cohort, and finally identified five novel significant association signals (rs11119445: 3’ of SERTAD4, P = 6.44 × 10−14; rs227227 and rs12561877: intron of SYT14, P = 5.02 × 10−13 and 2.80 × 10−11, respectively; rs643118: intron of TRAF3IP3, P = 4.45 × 10−6; rs2095293: intron of NR6A1, P = 2.98 × 10−5). The mean (standard deviation) of the weighted genetic risk score (wGRS) from these SNPs was 1.83 (0.65) for NSCL/P cases and 1.58 (0.68) for controls, respectively (P = 2.67 × 10−16). Rs643118 was identified as a shared susceptible factor of NSCL/P among Asians and Europeans, while rs227227 may contribute to the risk of NSCL/P as well as NSCPO. In addition, sertad4 knockdown zebrafish models resulted in down‐regulation of sox2 and caused oedema around the heart and mandibular deficiency, compared with control embryos. Taken together, this study has improved our understanding of the genetic susceptibility to NSCL/P and provided further clues to its aetiology in the Chinese population.

Purpose of Review Mitochondria are recognized to be one of the most important organelles in chondrocytes for their role in triphosphate (ATP) generation through aerobic phosphorylation. Mitochondria also participate in many intracellular processes involving modulating reactive oxygen species (ROS), responding to instantaneous hypoxia stress, regulating cytoplasmic transport of calcium ion, and directing mitophagy to maintain the homeostasis of individual chondrocytes. Designs To summarize the specific role of mitochondria in chondrocytes, we screened related papers in PubMed database and the search strategy is ((mitochondria) AND (chondrocyte)) AND (English [Language]). The articles published in the past 5 years were included and 130 papers were studied. Results In recent years, the integrity of mitochondrial structure has been regarded as a prerequisite for normal chondrocyte survival and defect in mitochondrial function has been found in cartilage-related diseases, such as osteoarthritis (OA) and rheumatoid arthritis (RA). However, the understanding of mitochondria in cartilage is still largely limited. The mechanism on how the changes in mitochondrial structure and function directly lead to the occurrence and development of cartilage-related diseases remains to be elusive. Conclusion This review aims to summarize the role of mitochondria in chondrocytes under the physiological and pathological changes from ATP generation, calcium homeostasis, redox regulation, mitophagy modulation, mitochondria biogenesis to immune response activation. The enhanced understanding of molecular mechanisms in mitochondria might offer some new cues for cartilage remodeling and pathological intervention.

OBJECTIVE Non-syndromic tooth agenesis (NSTA) may share common genetic factors with non-syndromic cleft lip with or without cleft palate (NSCL/P). Single-nucleotide polymorphisms (SNPs) were associated with individual's susceptibility to these anomalies. We selected five NSCL/P-associated SNPs from our previous genome-wide association study (GWAS) to test for the associations with NSTA. MATERIALS AND METHODS A total of 677 NSTA cases and 1,144 healthy controls were recruited in this case-control study. Five genome-wide NSCL/P-associated SNPs (rs2235371, rs7078160, rs8049367, rs4791774, and rs13041247) were genotyped by TaqMan platform and evaluated for the associations with NSTA using plink software. RESULTS No significant associations between these SNPs and risk of NSTA were observed in the overall analysis and subgroup analysis with the number of missing teeth. However, in the subgroup analysis by tooth position, rs8049367 was nominally associated with mandibular premolar agenesis (Dominant model: ORdom = 0.66, 95% CIdom = 0.47-0.93, pdom = 0.016; Heterozygote model: ORhet = 0.60, 95% CIhet = 0.41-0.88, Phet = 0.008). Rs4791774 showed a nominal association with congenitally missing maxillary canine (Dominant model: ORdom = 0.53, 95% CIdom = 0.28-0.98, pdom = 0.041; Heterozygote model: ORhet = 0.50, 95% CIhet = 0.26-0.97, Phet = 0.041) and premolar (Additive model: OR = 0.59, 95% CI = 0.36-0.96, p = 0.035). CONCLUSION This study showed that NSCL/P susceptible loci rs8049367 and rs4791774 were probably associated with the risk of NSTA.

Connexin 43 (Cx43)-mediated gap junction intercellular communication (GJIC) plays a crucial role in the pathology and physiology of joint tissues. Transforming growth factor-β2 (TGF-β2), one of the potent regulatory factors in chondrocytes, plays a key role in the regulation of cell cycle and development of joint diseases. However, it is still unknown how TGF-β2 mediates GJIC in chondrocytes. The aim of this study was to explore the potential mechanism by which TGF-β2 regulates GJIC in chondrocytes. CCK-8 assays and scratch assays were performed to define the role of TGF-β2 on cell proliferation and migration. The scrape loading/dye transfer assay and scanning electron microscopy (SEM) were used to verify the effect of TGF-β2 on GJIC between chondrocytes. qPCR was performed to analyse the expression of genes in the gap junction protein family in chondrocytes. The expression of the Cx43 protein and phosphorylated Smad3 (p-Smad3) was evaluated by western blot assay. Immunofluorescence staining was used to explore p-Smad3 signalling pathway activation and Cx43 distribution. From these experiments, we found that the Cx43 protein was the most highly expressed member of the gap junction protein family in chondrocytes. We also found that TGF-β2 facilitated cell-to-cell communication in chondrocytes by upregulating Cx43 expression in chondrocytes. Finally, we found that TGF-β2 activated Smad3 signalling and promoted the nuclear aggregation of p-Smad3. Inhibition experiments by SIS3 also confirmed that TGF-β2-mediated GJIC through p-Smad3 signalling. For the first time, this study confirmed that TGF-β2 could regulate the formation of Cx43-mediated GJIC in chondrocytes via the canonical p-Smad3 signalling pathway.

Background Non-syndromic supernumerary teeth (NSST) or hyperdontia may share common genetic determinants with non-syndromic cleft lip with or without palate (NSCL/P). The aim of this study was to test the associations between five genome-wide-associated NSCL/P-susceptible single nucleotide polymorphisms (SNPs) (rs2235371, rs7078160, rs8049367, rs4791774, and rs13041247) and the occurrence of NSST. Materials and methods A total of 163 cases and 326 controls were recruited and their genomic DNA was extracted from blood samples. Five NSCL/P-susceptible SNPs (rs2235371, rs7078160, rs8049367, rs4791774, and rs13041247) were genotyped by TaqMan method. Odds ratio (OR) and 95% confidence interval (CI) were used to estimate the associations between the SNPs and the risk of NSST by PLINK software. Results Rs4791774 (A > G) and rs13041247 (T > C) were associated with risk of NSST (rs4791774: Padd = 0.011, OR, 95% CI = 0.62, 0.43-0.90; rs13041247: Phomo = 0.031, OR, 95% CI = 1.79, 1.05-3.05) and one supernumerary tooth (rs4791774: Pdom = 0.009, OR, 95% CI = 0.56, 0.36-0.87; rs13041247: Phomo = 0.034, OR, 95% CI = 1.82, 1.05-3.15). Rs4791774 (A > G) was also showed association with risk of upper arch supernumerary teeth only (Padd = 0.010, OR, 95% CI = 0.60, 0.41-0.89). Conclusion Non-syndromic cleft lip with or without palate-susceptible loci rs4791774 (A > G) and rs13041247 (T > C) were associated with the risk of supernumerary teeth.

Objective Non-syndromic supernumerary teeth (NSST) are a common type of dental anomaly. microRNAs (miRNAs) play an important role in craniofacial and tooth development. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) of miRNAs may be associated with the susceptibility of NSST. Materials and methods Four miRNA SNPs (rs2910164, rs11614913, rs2043556, and rs2682818) were selected, and their associations with NSST susceptibility were evaluated in a case-control study (163 NSST patients and 326 healthy controls). Results rs2910164 was significantly associated with a risk of lower NSST (additive model: OR = 4.00, 95 % CI = 1.76–9.09, P = 0.001), and rs2682818 showed nominal association with a risk of upper NSST (additive model: OR = 1.40, 95 % CI = 1.02–1.91, P = 0.037) and NSST among male patients (additive model: OR = 1.62, 95 % CI = 1.08–2.43, P = 0.020). Conclusion Genetic variants of miR-146a/rs2910164 and miR-618/rs2682818 were likely associated with the risk of NSST in the Chinese population.

Nonsyndromic cleft lip with/without cleft palate (NSCL/P) is one of the most common human congenital defects. Rs2262251 (G>C) in long noncoding RNA (lncRNA) RP11-462G12.2 is in high linkage disequilibrium with rs8049367, which was identified in our previous genome-wide association study on NSCL/P, and is a potential causative single-nucleotide polymorphism (SNP) for NSCL/P. To test these hypotheses, rs2262251 was evaluated in another cohort of 1,314 cases and 1,259 controls. Rs2262251 was associated with NSCL/P risk (p = .003). However, no association was detected for cleft palate only. SNP rs2262251 affected the structure and expression of lncRNA RP11-462G12.2 in HEK293 and HEPM cells and in lip tissues from patients with NSCL/P. Overexpression of the rs2262251 G allele contributed to reducing the number of cells in the G0/G1 phase, inhibiting cell apoptosis, and promoting cell proliferation in vitro. The rs2262251 C allele regulated the expression of miR-744-5p and its target gene IQSEC2, both of which were expressed in human lip tissues, and showed reverse correlation during mouse lip development. Taken together, these findings suggest that rs2262251 is associated with the risk of NSCL/P and participates in a lncRNA-miRNA-mRNA regulatory axis in which miR-744-5p and IQSEC2 combine to control NSCL/P development.