Research Spotlight

Liang, Y., Z. Hu, B. Chang and X. Liu (2019). “Quantitative characterizations of the Sharpey’s fibers of rat molars.” J Periodontal Res Dec 1. [Epub ahead of print].

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BACKGROUND AND OBJECTIVE: The Sharpey’s fibers of periodontal ligament (PDL) anchor the PDL to alveolar bone and cementum and are essential for the function of PDL. While qualitative analyses of the Sharpey’s fibers have been widely explored, a comprehensive quantitative characterization of the Sharpey’s fibers is not available. In this work, we selected rat molars as a model and comprehensively characterized the PDL Sharpey’s fibers (diameter, density, length, embedding angle, and insertion angle). MATERIALS AND METHODS: A total of 24 rat mandibular molars, eight maxillary first molars, and their surrounding alveolar bone were harvested, fixed, rendered anorganic and observed under scanning electron microscopy (SEM). The mandibles and maxillae (n = 4) were harvested, processed, sectioned, and stained with Sirius red for histological observation. SEM images were used for quantitative analyses of diameters and densities of the Sharpey’s fibers, while Sirius red staining images were used to measure lengths and angles. The Sharpey’s fibers were comprehensively characterized in terms of positions (cervical, middle, and apical thirds), PDL fiber groups (alveolar crest, horizontal, oblique, apical, and interradicular groups), sides (cementum and bone sides), and teeth (mandibular first, second, third molars, and maxillary first molar). RESULTS: Our results showed that the characteristic parameters of the Sharpey’s fibers varied in different positions, fiber groups, sides, and teeth. Specifically, the median diameter of the Sharpey’s fibers on the bone side was significantly greater than that on the cementum side, while the median density of the Sharpey’s fibers on the bone side was significantly lower than that on the cementum side, regardless of the positions and teeth. For the same tooth, the median length of the embedded Sharpey’s fibers on the bone side was more than two times greater than that on the cementum side. Among all fiber groups, the alveolar crest group had the maximum length of the Sharpey’s fibers on the bone side and the minimal length of the Sharpey’s fibers on the cementum side. There is an approximate 5-15 degrees difference between the embedding angle and the insertion angle in each group. The oblique group had the smallest embedding angles on both the bone and cementum sides. CONCLUSION: This study provides a comprehensive and quantitative characterization of the Sharpey’s fibers using rat molars as a model. Overall, these parameters varied according to different vertical positions, fiber groups, teeth, and jawbones. The quantitative information of the Sharpey’s fibers presented in this work facilitates our understanding of PDL functions and advances the development of biomimetic materials for periodontal tissue regeneration.

Li, H., Y. Jing, R. Zhang, Q. Zhang, J. Wang, A. Martin and J. Q. Feng (2019). “Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone cells via a sharp increase in beta-catenin.” Bone Nov 18;131:115151. [Epub ahead of print].

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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.

Groppe, J. C. (2019). “Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy.” Expert Opin Drug Discov 14(12): 1237-1253.

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Introduction: Protein kinases are a major target for small-molecule drug development. However, relatively few compounds are free of off-target toxicity and reach the clinic. Because the 500-plus kinases share conserved ATP-binding clefts, the site targeted by competitive inhibitors, generation of specific therapeutics remains a nearly intractable challenge. Areas covered: Inducing degradation, instead of inhibition by occupancy-driven drugs, is an emerging strategy that offers the long-sought specificity, as well as mechanistic benefits. Currently approved inhibitors require steady-state binding and leave proteins intact for interactions in multi-protein complexes. After a general background about induced protein degradation, perspectives on protein kinases are provided. Expert opinion: Induced degradation by state-of-the-art compounds (proteolysis-targeting chimeras, PROTACs) has been shown for protein kinases, albeit in early pre-clinical stages. Further work is required to expand the number of enzymes that could be exploited to direct proteins for degradation by ubiquitylation. In addition, despite the simple modularity of the chimeras, generation of hits will require empirical approaches due to the role of protein-protein interactions and distribution of tagging sites. However, given the advantages of degradation, drug discovery efforts targeting protein kinases should increasingly shift toward generation and screening of inducers of degradation and away from occupancy-based inhibitors of old.

Azarpazhooh, A., A. R. Diogenes, A. F. Fouad, G. N. Glickman, M. K. Kang, A. Kishen, L. Levin, R. S. Roda, C. M. Sedgley, F. R. Tay and K. M. Hargreaves (2019). “Insights into the January 2020 Issue of the Journal of Endodontics.” J Endod Nov 29. [Epub ahead of print].

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Welcome to the January 2020 issue of the Journal of Endodontics ( JOE ). Here, we share some of our favorite articles that are published in this issue of the journal. We hope you look forward to reading these and other articles in JOE. [Excerpt from Article].

Azarpazhooh, A., A. R. Diogenes, A. F. Fouad, G. N. Glickman, M. K. Kang, A. Kishen, L. Levin, R. S. Roda, C. M. Sedgley, F. R. Tay and K. M. Hargreaves (2019). “Insights into the December 2019 Issue of the Journal of Endodontics.” J Endod 45(12): 1433-1434.

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Welcome to the December 2019 issue of the Journal of Endodontics ( JOE ). Here, we share some of our favorite articles that are published in this issue of the journal. We hope you look forward to reading these and other articles in JOE. [Excerpt from Article].