Ablation of Discoidin Domain Receptor 1 Predisposes Mice to Periodontitis
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Date
2019-03
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Abstract
The discoidin domain receptors, DDR1 and DDR2, are non-integrin collagen receptors belonging to a family of tyrosine kinases. DDRs regulate cell attachment, migration, and differentiation, and their extracellular domains affect collagen fibrillogenesis and mineralization. We hypothesized that DDR1 plays an important role in dentoalveolar development and function. Radiography, micro-computed tomography (micro-CT), histology, histomorphometry, in situ hybridization (ISH), immunohistochemistry (IHC), and quantitative PCR (qPCR) were used to analyze Ddr1 knockout (Ddr1-/-) mice and wild-type (WT) controls at 1 and 9 months, and to assess Ddr1/DDR1 mRNA expression in mouse and human tissues. Radiographic images showed normal molars, but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1-/- mice vs. WT controls at 9 months. Histological, histomorphometric, and micro-CT analyses of Ddr1-/- and WT mandibular first molars confirmed no differences in dimensions or mineral densities of enamel or dentin. Total volumes (TV) and bone volumes (BV) of subchondral and ramus bone of Ddr1-/- vs. WT condyles were increased 70-170% (p<0.01-0.0001), and bone volume fraction (BV/TV) was reduced 10-15% (p<0.01-0.001), at 1 and 9 months. There were no differences in alveolar bone volume at 1 month, but at 9 months severe periodontal defects and significant alveolar bone loss (14%; p<0.0001) were evident in Ddr1-/- vs. WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, loss-of-attachment, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, up-regulation of cytokines including macrophage colony-stimulating factor (Csf1), and 3-fold increased osteoclast numbers (p<0.05) in Ddr1-/- vs. WT periodontia at 9 months. ISH and qPCR in WT mouse tissues revealed highest Ddr1 expression in epithelium, including basal cell layers of the oral and junctional epithelia, and we confirmed a similar expression pattern in human oral epithelium. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to spontaneous periodontitis.
Description
Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
DDR1, Micro-computed tomography, Periodontitis, Bone