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Ectopic mineralisation of the mandibular symphysis in ENT1 knockout mice: A model of dystrophic calcification.

ABSTRACT: Equilibrative nucleoside transporter 1 (ENT1) transfers nucleosides, such as adenosine, across plasma membranes. We reported previously that mice lacking ENT1 (ENT1 ^-/- ) exhibit progressive ectopic calcification of spinal tissues-a phenotype resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. Our objective was to investigate potential calcification of orofacial tissues in ENT1 ^-/- mice. Heads of wild-type mice and ENT1 ^-/- mice from 3 to 17 months were evaluated using microcomputed tomography (μCT). Some heads were decalcified and processed for histological assessment. Other heads were examined using energy dispersive X-ray spectroscopy and micro X-ray diffraction. Using μCT, ENT1 ^-/- mice showed extensive radiopaque lesions within the mandibular symphysis, the severity of which increased with advancing age. Histologically, at 6 months these ectopic radiopacities were found to correspond to acellular, amorphous, eosinophilic material, with no evidence of inflammatory cells. Because lesions were localised to the symphysis, we identified early pathological changes at 3 months and observed that lesions initiated specifically within the fibrocartilage pad. Energy-dispersive X-ray spectroscopy of ectopic lesions revealed large amounts of calcium and phosphorous in a molar ratio of ~1.59, and X-ray diffraction profiles matched that of calcium-deficient hydroxyapatite. This is the first characterisation of ectopic calcifications within the mandibular symphysis of ENT1 ^-/- mice, indicating a role for ENT1 and adenosine metabolism in regulating calcification of fibrocartilaginous tissues. Moreover, these murine lesions resemble areas of dystrophic calcification in the spinal tissues of humans with DISH. Importantly, ectopic calcifications develop in a reproducible temporal pattern within a well-defined anatomical region and, thus, provide a model for determining the cellular and molecular pathways underlying ectopic calcification in DISH and related disorders.

SUBMITTER: Fournier DE

PROVIDER: S-EPMC8253951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe primary objective of this retrospective study was to document the normal variation of clinical mobility of the mandibular symphysis in dogs, and evaluate possible associations with breed, bodyweight, age, sex, and skull morphology. Secondarily, the radiographic appearance of the mandibular symphysis and possible associations with the analyzed data were also evaluated.MethodsMedical records of dogs that underwent anesthetic procedures for maxillofacial, oral and dental evaluation from April 2015 to December 2021 were included.Results567 dogs of 95 different breeds were included, with a total of 695 evaluations. Body weight ranged from 0.8 kg to 79 kg (median 14.4 kg) and age from 3 months to 16 years and 4 months (median 6 years and 9 months). Clinical mobility was evaluated under general anesthesia using a 0 to 3 scale, in lateromedial (LM) and dorsoventral (DV) directions. The symphysis was radiographically classified as being fused or open. The open symphyses were further radiographically divided in having parallel or divergent margins. At the time of the first evaluation DV mobility was 0 in 551 cases (97.2%) and 1 in 16 cases (2.8%). LM mobility was 0 in 401 cases (70.7%), 1 in 148 cases (26.1%) and 2 in 18 cases (3.2%). There was not a significant change in mobility over time for cases examined more than once (P= 0.76). All cases had an intraoral radiographic examination. 83.8% of the radiographs were included in the statistical analysis. Two symphyses (0.4%) were classified as fused and 473 (99.6%) as open, 355 (74.7%) having divergent margins and 118 (24.8%) parallel margins. Logistic regression models exploring factors that affected DV and LM mobility were statistically significant (P < 0.0001; P < 0.0001), with an increase in LM mobility predicting an increase in DV mobility, and vice versa. An increase in age and in bodyweight was associated with a decrease in mobility. There was no statistical difference in clinical mobility across specific breeds or sexes. Increased probability of a divergent symphysis and increased DV mobility was found to be associated with a brachycephalic conformation. The increase in LM mobility was comparatively higher in small brachycephalic breeds compared with larger brachycephalic breed.DiscussionThe majority of the cases showed little to no mobility of the mandibular symphysis and radiographically bony fusion can be rarely seen.

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Ectopic mineralisation of the mandibular symphysis in ENT1 knockout mice: A model of dystrophic calcification.

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