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

Abstract

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.

Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons

“…We designed a new conditional transgenic mouse that overexpresses TNF-α specifically in nociceptive neurons using the Cre-loxP system. Previously, others transgenic mouse models has been created using the same pCLE vector, such as huntingtin-interacting protein-1 (HIP-1) [3], TGF-β1 glo mice [13], and recently TNF-α glo mice in odontoblast and osteoclast cells [12]. To conditionally overexpress TNF-α in nociceptive neurons, we bred TNF-α glo mice with Nav1.8-Cre mice, which are known to express Cre in all small-diameters neurons and a small percentage of large-diameter nociceptive neurons in the DRG and TG [1].…”

Anti–nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery–induced pain

“…For example, currently the most commonly used endpoint in skeletal pain behaviors is skin hypersensitivity as assessed by von Frey (mechanical testing) or the Hargreaves method (thermal) [2; 20; 51; 67]. While it may be peripheral and/or central sensitization [15; 21; 29; 50; 60; 64] that is driving this skeletal injury induced skin hypersensitivity, from the perspective of a patient with skeletal pain due to osteoarthritis or TKA/THA, evoked skin hyperalgesia is rarely the major pain complaint [18; 55; 62]. Rather the major complaint of patients with orthopedic surgery pain is the spontaneous pain that arises upon use of the bone/joint that interferes with their quality of life, functional status, and ability to participate in the needed physical therapy and rehabilitation [10].…”

17β-Estradiol Inhibites Tumor Necrosis Factor-α Induced Apoptosis of Human Nucleus Pulposus Cells via the PI3K/Akt Pathway

“…As we know, TNF-α, an inflammatory cytokine, is involved in the process of intervertebral disc degeneration [11–15]. However, 17β-E2 has been proven to have an effect on lowering intervertebral disc degeneration in previous studies [23,24].…”

“…Etiologically, inflammatory cytokines including matrix metalloproteinases (MMPs), IL-1β, IL-6, TNF-α, nitric oxide, and prostaglandin E2 seem to be involved in the process of IVDD leading to loss of cells and ECM [11,12]. Among these inflammatory cytokines, TNF-α is known as a pro-inflammatory cytokine for NPCs.…”