Conditional TNF-alpha Overexpression in the Tooth and Alveolar Bone Results in Painful Pulpitis and Osteitis

Abstract

Tumor necrosis factor-alpha(TNF-alpha) is a proalgesic cytokine that is commonly expressed following tissue injury. TNF-alpha expression not only promotes inflammation but can also lead to pain hypersensitivity in nociceptors. With the established link between TNF-alpha 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-alpha(glo)) that could be used to conditionally overexpress TNF-alpha. These mice were bred with a dentin matrix protein 1 (DMP1)-Cre line for overexpression of TNF-alpha 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-alpha(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-alpha(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-alpha(glo) mice, we have shown that TNF-alpha expression alone can produce inflammation similar to pulpitis and osteitis and that this mouse model can be used to study dental inflammatory pain.