Research Spotlight

Ma, Y., Liu, S., Shu, H., Crawford, J., Xing, Y. and Tao, F. (2020). “Resveratrol alleviates temporomandibular joint inflammatory pain by recovering disturbed gut microbiota.” Brain Behav Immun Jan 27. [Epub ahead of print].

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Patients with temporomandibular disorders (TMDs) often experience persistent facial pain. However, the treatment of TMD pain is still inadequate. In recent years, the disturbance of gut microbiota has been shown to play an important role in the pathogenesis of different neurological diseases including chronic pain. In the present study, we investigated the involvement of gut microbiota in the development of temporomandibular joint (TMJ) inflammation. Intra-temporomandibular joint injection of complete Freund’s adjuvant (CFA) was employed to induce TMJ inflammation. Resveratrol (RSV), a natural bioactive compound with anti-inflammatory property, was used to treat the CFA-induced TMJ inflammation. We observed that CFA injection not only induces persistent joint pain, but also causes the reduction of short-chain fatty acids (SCFAs, including acetic acid, propionic acid and butyric acid) in the gut as well as decreases relevant gut bacteria Bacteroidetes and Lachnospiraceae. Interestingly, systemic administration of RSV (i.p.) dose-dependently inhibits CFA-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and these gut bacteria. Moreover, CFA injection causes blood-brain barrier (BBB) leakage, activates microglia and enhances tumor necrosis factor alpha (TNFalpha) release in the spinal trigeminal nucleus caudalis (Sp5C). The RSV treatment restores the BBB integrity, inhibits microglial activation and decreases the release of TNFalpha in the Sp5C. Furthermore, fecal microbiota transplantation with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammation. Taken together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating such pain.

Logan, S. M. and Benson, M. D. (2020). “Medial epithelial seam cell migration during palatal fusion.” J Cell Physiol 235(2): 1417-1424.

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The mammalian secondary palate forms from two shelves of mesenchyme sheathed in a single-layered epithelium. These shelves meet during embryogenesis to form the midline epithelial seam (MES). Failure of MES degradation prevents mesenchymal confluence and results in a cleft palate. Previous studies indicated that MES cells undergo features of epithelial-to-mesenchymal transition (EMT) and may become migratory as part of the fusion mechanism. To detect MES cell movement over the course of fusion, we imaged the midline of fusing embryonic ephrin-B2/GFP mouse palates in real time using two-photon microscopy. These mice express an ephrin-B2-driven green fluorescent protein (GFP) that labels the palatal epithelium nuclei and persists in those cells through the time window necessary for fusion. We observed collective migration of MES cells toward the oral surface of the palatal shelf over 48 hr of imaging, and we confirmed histologically that the imaged palates had fused by the end of the imaged period. We previously reported that ephrin reverse signaling in the MES is required for palatal fusion. We therefore added recombinant EphA4/Fc protein to block this signaling in imaged palates. The blockage inhibited fusion, as expected, but did not change the observed migration of GFP-labeled cells. Thus, we uncoupled migration and fusion. Our data reveal that palatal MES cells undergo a collective, unidirectional movement during palatal fusion and that ephrin reverse signaling, though required for fusion, controls aspects of the fusion mechanism independent of migration.

Li, H., Jing, Y., Zhang, R., Zhang, Q., Wang, J., Martin, A. and Feng, J. Q. (2020). “Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone cells via a sharp increase in beta-catenin.” Bone 131: 115151.

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Dentin matrix protein 1 (DMP1) is primarily expressed in osteocytes, although a low level of DMP1 is also detected in chondrocytes. Removing Dmp1 in mice or a mutation in humans leads to hypophosphatemic rickets (identical to X-linked hypophosphatemia). The deformed skeletons were currently thought to be a consequence of an inhibition of chondrogenesis (leading to an accumulation of hypertrophic chondrocytes and a failure in the replacement of cartilage by bone). To precisely study the mechanisms by which DMP1 and phosphorus control temporomandibular condyle formation, we first showed severe malformed condylar phenotypes in Dmp1-null mice (great expansions of deformed cartilage layers and subchondral bone), which worst as aging. Next, we excluded the direct role of DMP1 in condylar hypertrophic-chondrogenesis by conditionally deleting Dmp1 in hypertrophic chondrocytes using Col10a1-Cre and Dmp1 loxP mice (displaying no apparent phosphorous changes and condylar phenotype). To address the mechanism by which the onset of endochondral phenotypes takes place, we generated two sets of tracing lines in the Dmp1 KO background: AggrecanCreERT2-ROSA-tdTomato and Col 10a1-Cre-ROSA-tdTomato, respectively. Both tracing lines displayed an acceleration of chondrogenesis and cell trans-differentiation from chondrocytes into bone cells in the Dmp1 KO. Next, we showed that administrations of neutralizing fibroblast growth factor 23 (FGF23) antibodies in Dmp1-null mice restored hypophosphatemic condylar cartilage phenotypes. In further addressing the rescue mechanism, we generated compound mice containing Col10a1-Cre with ROSA-tdTomato and Dmp1 KO lines with and without a high Pi diet starting at day 10 for 39 days. We demonstrated that hypophosphatemia leads to an acceleration of chondrogenesis and trans-differentiation of chondrocytes to bone cells, which were largely restored under a high Pi diet. Finally, we identified the causative molecule (beta-catenin). Together, this study demonstrates that the Dmp1-null caused hypophosphatemia, leading to acceleration (instead of inhibition) of chondrogenesis and bone trans-differentiation from chondrocytes but inhibition of bone cell maturation due to a sharp increase in beta-catenin. These findings will aid in the future treatment of hypophosphatemic rickets with FGF23 neutralizing antibodies.

Kabani, F. A., Stockbridge, E. L., Berly Varghese, B. and Loethen, A. D. (2020). “Acculturation and the oral health of a nationally representative sample of Hispanic children in the United States: an analysis of 2011-2012 National Survey of Children’s Health data.” BMC Public Health 20(1): 111.

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BACKGROUND: Oral disease is a serious public health issue, and Hispanic children in the United States (US) are more likely than children of other racial/ethnic groups to experience dental caries. Although Hispanic children are a growing segment of the US population there is limited research on the association between acculturation and oral health outcomes in this population. This study examined the associations between household acculturation and pediatric oral health in the Hispanic population using a nationally representative sample of children. METHODS: Data from the 2011-2012 National Survey of Children’s Health were analyzed; analyses included Hispanic children ages 1 to 17. Household acculturation was assessed with a combination of language and parental nativity, while oral health was assessed via parents’/guardians’ reports of children’s dental caries. Logistic regression was used to examine the association between acculturation and oral health, adjusting for other demographic and social determinants of pediatric oral health. We assessed significance at the p < 0.05 level, and all analyses accounted for the survey's complex sample design. RESULTS: Analyses included 9143 Hispanic children. In total, 24.9% (95% CI: 22.9-27.0%) experienced dental caries, and there were significant associations between household acculturation and oral health. In unadjusted analyses, 32.0% (95% CI: 28.9-35.4%) of children in low acculturation households, 20.3% (95% CI: 16.0-25.4%) of children in moderate acculturation households, and 16.9% (95% CI: 14.2-20.0%) of children in high acculturation households experienced dental caries (p < 0.001). In adjusted analyses, children in high acculturation households were significantly less likely than those in low acculturation households to experience dental caries (p < 0.001; OR = 0.50; 95% CI: 0.35-0.70). The difference between children in moderate and low acculturation households approached but did not reach statistical significance (p = 0.057; OR = 0.69; 95% CI: 0.48-1.01). CONCLUSIONS: A dose-response relationship was observed between household acculturation and the oral health of Hispanic children in the US. As acculturation increases, the likelihood of a child experiencing dental caries decreases. These findings suggest that public health and community-based interventions intended to reduce oral health disparities in Hispanic children would likely be most impactful if the acculturation levels of the children's households are considered during program development.

Chan, S., Glickman, G. N., Woodmansey, K. F. and He, J. (2020). “Retrospective Analysis of Root-end Microsurgery Outcomes in a Postgraduate Program in Endodontics Using Calcium Silicate-based Cements as Root-end Filling Materials.” J Endod Jan 6. [Epub ahead of print].

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INTRODUCTION: The purpose of this retrospective study was to determine the clinical and radiographic outcomes of root-end microsurgery in a postgraduate program in endodontics using modern techniques and calcium silicate-based root-end filling materials (ProRoot MTA; Dentsply International, Johnson City, TN, and EndoSequence Root Repair Material [ERRM]; Brasseler USA, Savannah, GA) and to identify any potential prognostic factors that may have affected healing outcomes. METHODS: Clinical records and periapical radiographs were collected from patients who had undergone endodontic microsurgery between 2007 and 2018 in a postgraduate endodontic clinic with a minimum follow-up interval of 6 months. Either ProRoot MTA or ERRM was used as the root-end filling material. Outcomes were categorized into healed, healing, and nonhealing based on clinical and radiographic findings. Healed and healing cases were pooled and considered as successes, whereas nonhealing cases were considered as failures. RESULTS: A total of 129 patients with 142 teeth were included in the final analysis. Seventy-six cases were root-end filled with ProRoot MTA and 66 root-end filled with ERRM. The ProRoot MTA group had a success rate of 92.1%, and the ERRM group had a success rate of 92.4% with no significant difference between the groups (P > .05). Vertical root fracture was found to be the predominant cause of failure. No patient- or treatment-related factor was identified to have any significant impact on healing. CONCLUSIONS: High overall success can be achieved in a postgraduate endodontic program when either ProRoot MTA or ERRM is used as the root-end filling material.