Conditional TNF-α Overexpression in the Tooth and Alveolar Bone Results in Painful Pulpitis and Osteitis.
Tumor necrosis factor-α (TNF-α) is a proalgesic cytokine that is commonly expressed following tissue injury. TNF-α expression not only promotes inflammation but can also lead to pain hypersensitivity in nociceptors. With the established link between TNF-α and inflammatory pain, we identified its increased expression in the teeth of patients affected with caries and pulpitis. We generated a transgenic mouse model (TNF-α(glo)) that could be used to conditionally overexpress TNF-α. These mice were bred with a dentin matrix protein 1 (DMP1)-Cre line for overexpression of TNF-α in both the tooth pulp and bone to study oral pain that would result from subsequent development of pulpitis and bone loss. The resulting DMP1/TNF-α(glo) mice show inflammation in the tooth pulp that resembles pulpitis while also displaying periodontal bone loss. Inflammatory infiltrates and enlarged blood vessels were observed in the tooth pulp. Pulpitis and osteitis affected the nociceptive neurons innervating the orofacial region by causing increased expression of inflammatory cytokines within the trigeminal ganglia. With this new mouse model morphologically mimicking pulpitis and osteitis, we tested it for signs of oral pain with an oral function assay (dolognawmeter). This assay/device records the time required by a mouse to complete a discrete gnawing task. The duration of gnawing required by the DMP1/TNF-α(glo) mice to complete the task was greater than that for the controls; extended gnaw time in a dolognawmeter indicates reduced orofacial function. With the DMP1/TNF-α(glo) mice, we have shown that TNF-α expression alone can produce inflammation similar to pulpitis and osteitis and that this mouse model can be used to study dental inflammatory pain.
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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Hall
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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Sun
Laboratory of Cellular and Molecular Mechanisms of Pain, Faculty of Sciences, University of Chile, Santiago, Chile.
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Utreras
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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Prochazkova
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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Cho
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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Terse
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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Arany
NYU Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, School of Dentistry New York University College of Dentistry, New York, NY, USA.
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Dolan
NYU Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, School of Dentistry New York University College of Dentistry, New York, NY, USA.
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Schmidt
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA ashok.kulkarni@nih.gov.
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Kulkarni
D016301:Alveolar Bone Loss / Q000209:etiology / Q000378:metabolism; D000539:Alveolar Process / Q000378:metabolism*; D000818:Animals; D003731:Dental Caries / Q000378:metabolism; D003782:Dental Pulp / Q000098:blood supply; D004108:Dilatation, Pathologic / Q000473:pathology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000502:physiology; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D008409:Mastication / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000473:pathology; D009619:Nociceptors / Q000378:metabolism*; D010000:Osteitis / Q000209:etiology* / Q000378:metabolism; D011671:Pulpitis / Q000209:etiology* / Q000378:metabolism; D013997:Time Factors; D014070:Tooth / Q000378:metabolism*; D014098:Toothache / Q000378:metabolism; D014162:Transfection; D012668:Trigeminal Ganglion / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha
Cdk5; animal model; cytokine(s); facial pain; inflammation; toothache