Loss of Discoidin Domain Receptor 1 Predisposes Mice to Periodontal Breakdown

M. B. Chavez; T. N. Kolli; M. H. Tan; C. Zachariadou; C. Wang; M. C. Embree; E. J. Lira Dos Santos; F. H. Nociti; Y. Wang; D. N. Tatakis; G. Agarwal; B. L. Foster

doi:10.1177/0022034519881136

Loss of Discoidin Domain Receptor 1 Predisposes Mice to Periodontal Breakdown

M. B. Chavez, T. N. Kolli, M. H. Tan, C. Zachariadou, C. Wang, M. C. Embree, E. J. Lira Dos Santos, F. H. Nociti, Y. Wang, D. N. Tatakis, G. Agarwal, B. L. Foster

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, 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 transmission electron microscopy (TEM) were used to analyze Ddr1 knockout (Ddr1^−/−) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1/DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1^−/− mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1^−/− versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1^−/− versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P < 0.0001) were evident in Ddr1^−/− versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers (P < 0.05) in Ddr1^−/− versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown.

Original language	English (US)
Pages (from-to)	1521-1531
Number of pages	11
Journal	Journal of dental research
Volume	98
Issue number	13
DOIs	https://doi.org/10.1177/0022034519881136
State	Published - Dec 1 2019
Externally published	Yes

Bibliographical note

Funding Information:
Chavez M.B. 1 Kolli T.N. 1 Tan M.H. 1 Zachariadou C. 1 Wang C. 1 Embree M.C. 2 Lira Dos Santos E.J. 1 3 Nociti F.H. Jr. 3 Wang Y. 4 https://orcid.org/0000-0001-6327-3610 Tatakis D.N. 4 https://orcid.org/0000-0003-3731-2107 Agarwal G. 5 Foster B.L. 1 1 Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA 2 TMJ Biology and Regenerative Medicine Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA 3 Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas—UNICAMP, Piracicaba, SP, Brazil 4 Division of Periodontology, College of Dentistry, The Ohio State University, Columbus, OH, USA 5 Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA B.L. Foster, Biosciences Division, College of Dentistry, The Ohio State University, 4163 Postle Hall, 305 W. 12th Avenue, Columbus, OH 43210, USA. Email: [email protected] 10 2019 0022034519881136 © International & American Associations for Dental Research 2019 2019 International & American Associations for Dental Research The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, 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 transmission electron microscopy (TEM) were used to analyze Ddr1 knockout ( Ddr1 −/− ) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1 / DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1 −/− mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1 −/− versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1 −/− versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P < 0.0001) were evident in Ddr1 −/− versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers ( P < 0.05) in Ddr1 −/− versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown. extracellular matrix collagen(s) periodontal tissue/periodontium bone loss odontogenesis inflammation The Ohio State University College of Dentistry National Institute of Arthritis and Musculoskeletal and Skin Diseases https://doi.org/10.13039/100000069 AR 066110 National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 R01DE027639 edited-state corrected-proof We thank Dr. Ai “Andy” Ni (Biosciences Division, College of Dentistry, The Ohio State University) for statistical consultation. A supplemental appendix to this article is available online. Author Contributions M.B. Chavez, B.L. Foster, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; T.N. Kolli, E.J. Lira Dos Santos, F.H. Nociti Jr., contributed to data acquisition, analysis, and interpretation, critically revised the manuscript; M.H. Tan, C. Wang, contributed to data acquisition and analysis, critically revised the manuscript; C. Zachariadou, contributed to data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; M.C. Embree, contributed to design, data acquisition, analysis, and interpretation, critically revised the manuscript; Y. Wang, D.N. Tatakis, contributed to design, data acquisition, and analysis, critically revised the manuscript; G. Agarwal, contributed to design and data interpretation, critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work. This research was supported by a seed grant to B.L.F. from the Ohio State University College of Dentistry, grant R00AR066110 to B.L.F. from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/National Institutes of Health (NIH), and grant R01DE027639 from the National Institute of Dental and Craniofacial Research (NIDCR)/NIH. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. ORCID iDs D.N. Tatakis https://orcid.org/0000-0001-6327-3610 G. Agarwal https://orcid.org/0000-0003-3731-2107

Funding Information:
We thank Dr. Ai ?Andy? Ni (Biosciences Division, College of Dentistry, The Ohio State University) for statistical consultation.

Publisher Copyright:
© International & American Associations for Dental Research 2019.

Keywords

bone loss
collagen(s)
extracellular matrix
inflammation
odontogenesis
periodontal tissue/periodontium

Publisher link

10.1177/0022034519881136

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@article{edc8c92173854d79aab836e4752be4a8,

title = "Loss of Discoidin Domain Receptor 1 Predisposes Mice to Periodontal Breakdown",

abstract = "The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, 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 transmission electron microscopy (TEM) were used to analyze Ddr1 knockout (Ddr1−/−) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1/DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1−/− mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1−/− versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1−/− versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P < 0.0001) were evident in Ddr1−/− versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers (P < 0.05) in Ddr1−/− versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown.",

keywords = "bone loss, collagen(s), extracellular matrix, inflammation, odontogenesis, periodontal tissue/periodontium",

author = "Chavez, {M. B.} and Kolli, {T. N.} and Tan, {M. H.} and C. Zachariadou and C. Wang and Embree, {M. C.} and {Lira Dos Santos}, {E. J.} and Nociti, {F. H.} and Y. Wang and Tatakis, {D. N.} and G. Agarwal and Foster, {B. L.}",

note = "Funding Information: Chavez M.B. 1 Kolli T.N. 1 Tan M.H. 1 Zachariadou C. 1 Wang C. 1 Embree M.C. 2 Lira Dos Santos E.J. 1 3 Nociti F.H. Jr. 3 Wang Y. 4 https://orcid.org/0000-0001-6327-3610 Tatakis D.N. 4 https://orcid.org/0000-0003-3731-2107 Agarwal G. 5 Foster B.L. 1 1 Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA 2 TMJ Biology and Regenerative Medicine Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA 3 Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas—UNICAMP, Piracicaba, SP, Brazil 4 Division of Periodontology, College of Dentistry, The Ohio State University, Columbus, OH, USA 5 Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA B.L. Foster, Biosciences Division, College of Dentistry, The Ohio State University, 4163 Postle Hall, 305 W. 12th Avenue, Columbus, OH 43210, USA. Email: [email protected] 10 2019 0022034519881136 {\textcopyright} International & American Associations for Dental Research 2019 2019 International & American Associations for Dental Research The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, 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 transmission electron microscopy (TEM) were used to analyze Ddr1 knockout ( Ddr1 −/− ) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1 / DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1 −/− mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1 −/− versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1 −/− versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P < 0.0001) were evident in Ddr1 −/− versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers ( P < 0.05) in Ddr1 −/− versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown. extracellular matrix collagen(s) periodontal tissue/periodontium bone loss odontogenesis inflammation The Ohio State University College of Dentistry National Institute of Arthritis and Musculoskeletal and Skin Diseases https://doi.org/10.13039/100000069 AR 066110 National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 R01DE027639 edited-state corrected-proof We thank Dr. Ai “Andy” Ni (Biosciences Division, College of Dentistry, The Ohio State University) for statistical consultation. A supplemental appendix to this article is available online. Author Contributions M.B. Chavez, B.L. Foster, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; T.N. Kolli, E.J. Lira Dos Santos, F.H. Nociti Jr., contributed to data acquisition, analysis, and interpretation, critically revised the manuscript; M.H. Tan, C. Wang, contributed to data acquisition and analysis, critically revised the manuscript; C. Zachariadou, contributed to data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; M.C. Embree, contributed to design, data acquisition, analysis, and interpretation, critically revised the manuscript; Y. Wang, D.N. Tatakis, contributed to design, data acquisition, and analysis, critically revised the manuscript; G. Agarwal, contributed to design and data interpretation, critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work. This research was supported by a seed grant to B.L.F. from the Ohio State University College of Dentistry, grant R00AR066110 to B.L.F. from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/National Institutes of Health (NIH), and grant R01DE027639 from the National Institute of Dental and Craniofacial Research (NIDCR)/NIH. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. ORCID iDs D.N. Tatakis https://orcid.org/0000-0001-6327-3610 G. Agarwal https://orcid.org/0000-0003-3731-2107 Funding Information: We thank Dr. Ai ?Andy? Ni (Biosciences Division, College of Dentistry, The Ohio State University) for statistical consultation. Publisher Copyright: {\textcopyright} International & American Associations for Dental Research 2019.",

year = "2019",

month = dec,

day = "1",

doi = "10.1177/0022034519881136",

language = "English (US)",

volume = "98",

pages = "1521--1531",

journal = "Journal of dental research",

issn = "0022-0345",

publisher = "SAGE Publications Inc.",

number = "13",

}

TY - JOUR

T1 - Loss of Discoidin Domain Receptor 1 Predisposes Mice to Periodontal Breakdown

AU - Chavez, M. B.

AU - Kolli, T. N.

AU - Tan, M. H.

AU - Zachariadou, C.

AU - Wang, C.

AU - Embree, M. C.

AU - Lira Dos Santos, E. J.

AU - Nociti, F. H.

AU - Wang, Y.

AU - Tatakis, D. N.

AU - Agarwal, G.

AU - Foster, B. L.

N1 - Funding Information: Chavez M.B. 1 Kolli T.N. 1 Tan M.H. 1 Zachariadou C. 1 Wang C. 1 Embree M.C. 2 Lira Dos Santos E.J. 1 3 Nociti F.H. Jr. 3 Wang Y. 4 https://orcid.org/0000-0001-6327-3610 Tatakis D.N. 4 https://orcid.org/0000-0003-3731-2107 Agarwal G. 5 Foster B.L. 1 1 Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, USA 2 TMJ Biology and Regenerative Medicine Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA 3 Department of Prosthodontics and Periodontics, Division of Periodontics, Piracicaba Dental School, University of Campinas—UNICAMP, Piracicaba, SP, Brazil 4 Division of Periodontology, College of Dentistry, The Ohio State University, Columbus, OH, USA 5 Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA B.L. Foster, Biosciences Division, College of Dentistry, The Ohio State University, 4163 Postle Hall, 305 W. 12th Avenue, Columbus, OH 43210, USA. Email: [email protected] 10 2019 0022034519881136 © International & American Associations for Dental Research 2019 2019 International & American Associations for Dental Research The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, 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 transmission electron microscopy (TEM) were used to analyze Ddr1 knockout ( Ddr1 −/− ) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1 / DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1 −/− mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1 −/− versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1 −/− versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P < 0.0001) were evident in Ddr1 −/− versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers ( P < 0.05) in Ddr1 −/− versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown. extracellular matrix collagen(s) periodontal tissue/periodontium bone loss odontogenesis inflammation The Ohio State University College of Dentistry National Institute of Arthritis and Musculoskeletal and Skin Diseases https://doi.org/10.13039/100000069 AR 066110 National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 R01DE027639 edited-state corrected-proof We thank Dr. Ai “Andy” Ni (Biosciences Division, College of Dentistry, The Ohio State University) for statistical consultation. A supplemental appendix to this article is available online. Author Contributions M.B. Chavez, B.L. Foster, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; T.N. Kolli, E.J. Lira Dos Santos, F.H. Nociti Jr., contributed to data acquisition, analysis, and interpretation, critically revised the manuscript; M.H. Tan, C. Wang, contributed to data acquisition and analysis, critically revised the manuscript; C. Zachariadou, contributed to data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; M.C. Embree, contributed to design, data acquisition, analysis, and interpretation, critically revised the manuscript; Y. Wang, D.N. Tatakis, contributed to design, data acquisition, and analysis, critically revised the manuscript; G. Agarwal, contributed to design and data interpretation, critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work. This research was supported by a seed grant to B.L.F. from the Ohio State University College of Dentistry, grant R00AR066110 to B.L.F. from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/National Institutes of Health (NIH), and grant R01DE027639 from the National Institute of Dental and Craniofacial Research (NIDCR)/NIH. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. ORCID iDs D.N. Tatakis https://orcid.org/0000-0001-6327-3610 G. Agarwal https://orcid.org/0000-0003-3731-2107 Funding Information: We thank Dr. Ai ?Andy? Ni (Biosciences Division, College of Dentistry, The Ohio State University) for statistical consultation. Publisher Copyright: © International & American Associations for Dental Research 2019.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, 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 transmission electron microscopy (TEM) were used to analyze Ddr1 knockout (Ddr1−/−) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1/DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1−/− mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1−/− versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1−/− versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P < 0.0001) were evident in Ddr1−/− versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers (P < 0.05) in Ddr1−/− versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown.

AB - The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, 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 transmission electron microscopy (TEM) were used to analyze Ddr1 knockout (Ddr1−/−) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1/DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1−/− mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1−/− versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1−/− versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P < 0.0001) were evident in Ddr1−/− versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers (P < 0.05) in Ddr1−/− versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown.

KW - bone loss

KW - collagen(s)

KW - extracellular matrix

KW - inflammation

KW - odontogenesis

KW - periodontal tissue/periodontium

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U2 - 10.1177/0022034519881136

DO - 10.1177/0022034519881136

M3 - Article

C2 - 31610730

AN - SCOPUS:85074538763

SN - 0022-0345

VL - 98

SP - 1521

EP - 1531

JO - Journal of dental research

JF - Journal of dental research

IS - 13

ER -

Loss of Discoidin Domain Receptor 1 Predisposes Mice to Periodontal Breakdown

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