For decades, it has been widely accepted that hypertrophic chondrocytes undergo apoptosis prior to endochondral bone formation. However, very recent studies in long bone suggest that chondrocytes can directly transform into bone cells. Our initial in vivo characterization of condylar hypertrophic chondrocytes revealed modest numbers of apoptotic cells but high levels of antiapoptotic Bcl-2 expression, some dividing cells, and clear alkaline phosphatase activity (early bone marker). Ex vivo culture of newborn condylar cartilage on a chick chorioallantoic membrane showed that after 5 d the cells on the periphery of the explants had begun to express Col1 (bone marker). The cartilage-specific cell lineage-tracing approach in triple mice containing Rosa 26 tdTomato (tracing marker), 2.3 Col1 GFP (bone cell marker), and aggrecan Cre ERT2 (onetime tamoxifen induced) or Col10-Cre (activated from E14.5 throughout adult stage) demonstrated the direct transformation of chondrocytes into bone cells in vivo. This transformation was initiated at the inferior portion of the condylar cartilage, in contrast to the initial ossification site in long bone, which is in the center. Quantitative data from the Col10-Cre compound mice showed that hypertrophic chondrocytes contributed to ~80% of bone cells in subchondral bone, ~70% in a somewhat more inferior region, and ~40% in the most inferior part of the condylar neck (n = 4, P < 0.01 for differences among regions). This multipronged approach clearly demonstrates that a majority of chondrocytes in the fibrocartilaginous condylar cartilage, similar to hyaline cartilage in long bones, directly transform into bone cells during endochondral bone formation. Moreover, ossification is initiated from the inferior portion of mandibular condylar cartilage with expansion in one direction.

To date, attempts to regenerate a complete tooth, including the critical periodontal tissues associated with the tooth root, have not been successful. Controversy still exists regarding the origin of the cell source for cellular cementum (epithelial or mesenchymal). This disagreement may be partially due to a lack of understanding of the events leading to the initiation and development of the tooth roots and supportive tissues, such as the cementum. Osterix (OSX) is a transcriptional factor essential for osteogenesis, but its role in cementogenesis has not been addressed. In the present study, we first documented a close relationship between the temporal-and spatial-expression pattern of OSX and the formation of cellular cementum. We then generated 3.6 Col 1-OSX transgenic mice, which displayed accelerated cementum formation vs. WT controls. Importantly, the conditional deletion of OSX in the mesenchymal cells with two different Cre systems (the 2.3 kb Col 1 and an inducible CAG-CreER) led to a sharp reduction in cellular cementum formation (including the cementum mass and mineral deposition rate) and gene expression of dentin matrix protein 1 (DMP1) by cementocytes. However, the deletion of the OSX gene after cellular cementum formed did not alter the properties of the mature cementum as evaluated by backscattered SEM and resin-cast SEM. Transient transfection of Osx in the cementoblasts in vitro significantly inhibited cell proliferation and increased cell differentiation and mineralization. Taken together, these data support 1) the mesenchymal origin of cellular cementum (from PDL progenitor cells); 2) the vital role of OSX in controlling the formation of cellular cementum; and 3) the limited remodeling of cellular cementum in adult mice.

Understanding periodontal ligament (PDL) biology and developing an effective treatment for bone and PDL damage due to periodontitis have been longstanding aims in dental medicine. Here, we first demonstrated by cell lineage tracing and mineral doublelabeling approaches that murine PDL progenitor cells display a 2-and 3-fold higher mineral deposition rate than the periosteum and endosteum at the age of 4 weeks, respectively. We next proved that the pathologic changes in osteocytes (Ocys; changes from a spindle shape to round shape with a >50% reduction in the dendrite number/length, and an increase in SOST) are the key pathologic factors responsible for bone and PDL damage in periostin-null mice (a periodontitis animal model) using a newly developed 3-dimensional FITCImaris technique. Importantly, we proved that deleting the Sost gene (a potent inhibitor of WNT signaling) or blocking sclerostin function by using the mAb in this periodontitis model significantly restores bone and PDL defects (n = 4-5; P < 0.05). Together, identification of the key contribution of the PDL in normal alveolar bone formation, the pathologic changes of the Ocys in periodontitis bone loss, and the novel link between sclerostin and Wnt signaling in the PDL will aid future drug development in the treatment of patients with

SignificanceWe generated a novel conditional inducible mouse model of fibrous dysplasia (FD) by expressing mutant GNAS in skeletal stem cells (SSCs) in a temporally controlled and tissue-specific fashion. Typical FD bone lesions developed rapidly in mutant embryos and postnatal mice. GNAS promoted PKA activation and proliferation of SSCs along the osteogenic lineage but impaired their differentiation to mature osteoblasts and triggered increased osteoclastogenesis and bone resorption. FD lesions reverted on cessation of GNAS expression. Thus, GNAS mutation is sufficient and necessary for FD initiation and maintenance. This model provides a valuable opportunity to identify the molecular mechanism underlying FD progression and accelerate the development of more effective treatment options.

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Hydrogels with high mechanical strength and injectability have attracted extensive attention in biomedical and tissue engineering. However, endowing a hydrogel with both properties is challenging because they are generally inversely related. In this work, by constructing a multi‐hydrogen‐bonding system, a high‐strength and injectable supramolecular hydrogel is successfully fabricated. It is constructed by the self‐assembly of a monomeric nucleoside molecular gelator (2‐amino‐2′‐fluoro‐2′‐deoxyadenosine (2‐FA)) with distilled water/phosphate buffered saline as solvent. Its storage modulus reaches 1 MPa at a concentration of 5.0 wt%, which is the strongest supramolecular hydrogel comprising an ultralow‐molecular‐weight (MW < 300) gelator. Furthermore, it exhibits excellent shear‐thinning injectability, and completes the sol–gel transition in seconds after injection at 37 °C. The multi‐hydrogen‐bonding system is essentially based on the synergistic interactions between the double NH2 groups, water molecules, and 2′‐F atoms. Furthermore, the 2‐FA hydrogel exhibits excellent biocompatibility and antibacterial activity. When applied to rat molar extraction sockets, compared to natural healing and the commercial hemorrhage agent gelatin sponge, the 2‐FA hydrogel exhibits faster degradation and induces less osteoclastic activity and inflammatory infiltration, resulting in more complete bone healing. In summary, this study provides ideas for proposing a multifunctional, high‐strength, and injectable supramolecular hydrogel for various biomedical engineering applications.

Periostin plays multiple functions during development. Our previous work showed a critical role of this disulfide-linked cell adhesion protein in maintenance of periodontium integrity in response to occlusal load. In this study, we attempted to address whether this mechanical response molecule played a direct role in postnatal tooth development. Our key findings are 1) periostin is expressed in preodontoblasts, and odontoblasts; and the periostin-null incisor displayed a massive increase in dentin formation after mastication; 2) periostin is also expressed in the ameloblast cells, and an enamel defect is identified in both the adult-null incisor and molar; 3) deletion of periostin leads to changes in expression profiles of many non-collagenous protein such as DSPP, DMP1, BSP, and OPN in incisor dentin; 4) the removal of a biting force leads to reduction of mineralization, which is partially prevented in periostin-null mice; and 6) both in vitro and in vivo data revealed a direct regulation of periostin by TGF-␤1 in dentin formation. In conclusion, periostin plays a novel direct role in controlling postnatal tooth formation, which is required for the integrity of both enamel and dentin.It is well known that mechanical loading stimulates new bone formation, whereas unloading or disuse of bone (e.g. longtime bed rest, spaceflight, or cast immobilization) accelerates bone resorption. This adaptation is critical for bone modeling and remodeling (1). The anabolic degree to which the bone responds to physical activity has being associated with the intensity and loading magnitude of the exercise. Under normal conditions, strenuous exercise such as weightlifting yields thicker and denser bone compared with jogging and swimming; the latter two types of exercise are less forceful and produce less mechanical stimulus (2). A well-designed study by Tatsumi et al. (3) demonstrated that osteocytes are the key sensor controlling both bone formation and bone resorption in the unloading animal model. The accumulated evidence supports a recommendation by the National Osteoporosis Foundation: regular weight-bearing and muscle strengthening exercise is an effective countermeasure to fight against osteoporosis, a silent bone loss in the elderly population worldwide.The development and maintenance of the dental and periodontal structures are also directly influenced by mechanical stimuli (4). This stimulation can be the result of normal occlusal function or orthodontic treatment. It is well documented that during orthodontic treatment, tension on the side from which a tooth moves away results in the formation of new bone (i.e. osteogenic), while compression on the opposite site leads to bone resorption. This relationship seems contrary to the situation in the long bone where the loaded site is osteogenic and the unloaded site is resorptive (5). One of the interpretations regarding this difference between the alveolar bone and long bone is that the periodontal ligament (PDL), 3 a soft tissue located between the teeth and alveolar bone,...

In the current stage, there is no powerful evidence to support the use of biofeedback technology on sleep bruxism treatment. Contingent electrical stimulation which is defined as a kind of biofeedback modality shows no effect on reducing sleep bruxism episode compared with the no-treatment group. Although many studies support the efficacy of biofeedback treatment, more large sample-sized randomized controlled trials which adopt uniform outcome index are necessitated to verify its application.