The periodontal ligament (PDL) functions as an enthesis, a connective tissue attachment that dissipates strains created by mechanical loading. Entheses are mechanoresponsive structures that rapidly adapt to changes in their mechanical loading; here we asked which features of the PDL are sensitive to such in vivo loading. We evaluated the PDL in 4 physiologically relevant mechanical environments, focusing on mitotic activity, cell density, collagen content, osteogenic protein expression, and organization of the tissue. In addition to examining PDLs that supported teeth under masticatory loading and eruptive forces, 2 additional mechanical conditions were created and analyzed: hypoloading and experimental tooth movement. Collectively, these data revealed that the adult PDL is a remarkably quiescent tissue and that only when it is subjected to increased loads--such as those associated with mastication, eruption, and orthodontic tooth movement-does the tissue increase its rate of cell proliferation and collagen production. These data have relevance in clinical scenarios where PDL acclimatization can be exploited to optimize tooth movement.
Hypophosphatasia is caused by mutations of the tissue-non-specific alkaline phosphatase (TNSALP) gene with deficiency of dentin structure. The aim of this study was to examine whether TNSALP mutation in dental pulp cells contributes to dentin dysplasia in hypophosphatasia. Mutation analysis showed that compound heterozygous mutations of TNSALP were identified in three hypophosphatasia patients, including 3 novel mutation sites. Exfoliated teeth from the patients showed abnormal dentin mineralization and loss of cementum, as assessed by ground sections and scanning electron microscope analysis. Dental pulp cells isolated from one of the patients showed a significantly reduced TNSALP activity and mineralization capacity when compared with those in dental pulp cells from the unaffected individuals. Our results suggested that dentin dysplasia in hypophosphatasia may be associated with the decreased mineralization ability of dental pulp cells.
RUNX2 is a master osteogenic transcription factor, and mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Studies have revealed that RUNX2 is not only a downstream target of the bone morphogenetic protein (BMP) pathway but can also regulate the expression of BMPs. However, the underlying mechanism of the regulation of BMPs by RUNX2 remains unknown. In this project, we diagnosed a CCD patient with a 7.86-Mb heterozygous deletion on chromosome 6 containing all exons of RUNX2 by multiplex ligation-dependent probe amplification (MLPA) and whole-genome sequencing (WGS). Bone marrow mesenchymal stem cells (BMSCs) were further extracted from patient alveolar bone fragments (CCD-BMSCs), an excellent natural model to explore the possible mechanism. The osteogenic differentiation ability of CCD-BMSCs was severely affected by RUNX2 heterozygous deletion. Also, BMP4 decreased most in BMP ligands, and CHRDL1, a BMP antagonist, was abnormally elevated in CCD-BMSCs. Furthermore, BMP4 treatment essentially rescued the osteogenic capacity of CCD-BMSCs, and RUNX2 overexpression reversed the abnormal expression of BMP4 and CHRDL1. Notably, we constructed CRISPR/Cas9 Runx2+/m MC3T3-E1 cells, which simulated a variant in CCD-BMSCs, to exclude the interference of other gene deletions and the heterogeneity of the genetic background of primary cells, and verified all findings from the CCD-BMSCs. Moreover, the luciferase reporter experiment showed that RUNX2 could inhibit the transcription of CHRDL1. Through immunofluorescence, the inhibitory effect of CHRDL1 on BMP4/Smad signaling was confirmed in MC3T3-E1 cells. These results revealed that RUNX2 regulated the BMP4 pathway by inhibiting CHRDL1 transcription. We collectively identified a novel RUNX2/CHRDL1/BMP4 axis to regulate osteogenic differentiation and noted that BMP4 might be a valuable therapeutic option for treating bone diseases.
The aim of the present study was to investigate the short-term impact of an occlusal highspot on the occurrence of orofacial symptoms by collecting self-evaluation and using electromyography (EMG) evaluation. A rigid unilateral intercuspal occlusal highspot (A cast onlay of 0.5 mm) was placed on the right lower first molar of six adult volunteers (three males, three females), and remained for 6 days. Continuously all the induced orofacial symptoms were collected and the subjects scored the orofacial pain on a 10-cm visual analogue scale (VAS) during the placement of onlay. The surface EMG was recorded before the placement of onlay, during (on the 3rd and 6th day) and after the onlay was removed. Then the contractile symmetry of bilateral masseter (MAL, MAR) and anterior temporalis (TAL, TAR) was measured by using an asymmetry index. On the 3rd day of the placement of the occlusal highspot, all subjects complained of headache in right temporal region (mean VAS +/- s.d.=3.7+/-0.5); the activity of TAR at rest position of mandible increased significantly (P=0.027). In addition, on the 3rd and 6th day with the highspot the EMG activity of the tested muscles during maximal voluntary contraction (MVC) was significantly reduced; the asymmetry index of bilateral anterior temporalis during MVC was increased significantly (P(3rd)=0.028; P(6th)=0.046). A unilateral occlusal highspot may make the ipsilateral anterior temporalis become tenser at rest position. Furthermore, the activity of bilateral anterior temporalis becomes more unsymmetrical during MVC although there are inter-individual differences between subjects. The changes in muscular activity may have some relationship with the occurrence of tension-type headache in temporal region.
ObjectiveThe aim of this study was to explore the regulatory effect of RUNX2 mutation on dental follicle cells (DFCs) senescence and clarify the underlying mechanism. This study aimed to explore the basis for a novel mechanism of delayed permanent tooth eruption in cleidocranial dysplasia (CCD) patients.Materials and MethodsDental follicles were collected from a CCD patient and healthy controls. Senescence‐associated β‐galactosidase (SA‐β‐gal) staining, Ki67 staining, cell cycle assays, and senescence‐related gene and protein expression assays were performed to assess DFCs senescence. Western blotting was performed to detect the activation of mitogen‐activated protein kinase (MAPK) signalling pathways, and the molecular mechanism underlying RUNX2 regulating in DFCs senescence was explored.ResultsRUNX2 mutation inhibited the cellular senescence of DFCs from the CCD patient compared with healthy controls. Ki67 staining showed that mutant RUNX2 promoted DFCs proliferation, and cell cycle assays revealed that the healthy control‐derived DFCs arrested at G1 phase. RUNX2 mutation significantly downregulated senescence‐associated gene and protein expression. RUNX2 mutation suppressed ERK signalling pathway activation, an ERK inhibitor decreased healthy control‐derived DFCs senescence, and an ERK activator promoted CCD patient‐derived DFCs senescence.ConclusionsRUNX2 mutation delayed DFCs senescence through the ERK signalling pathway, which may be responsible for delayed permanent tooth eruption in CCD patients.
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