Summary Teeth are made up of many tissues, covered by inflexible and stubborn enamel. Unlike most other tissues, teeth become extremely sensitive to cold when they become inflamed. The mechanisms of this cold sensation are not understood. Here, we elucidate the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold detection. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing through the relative sensitivity of TRPC5 to intracellular calcium and lack of desensitization. Our data provide concrete functional evidence that equipping odontoblasts with the TRPC5 cold sensor expands the traditional functions of odontoblasts and makes it a previously unknown integral cellular component of the dental cold sensing system. |
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Odontoblasts , the cells that form a tooth’s dentin, have a newly discovered function: detecting cold, which can cause tooth pain; But scientists have also found a way to block the path to cold-sensitive teeth.
MASSACHUSETTS GENERAL HOSPITAL
BOSTON – Researchers report in Science Advances that they have discovered a new function for odontoblasts, the cells that form dentin, the shell beneath tooth enamel that covers the soft dental pulp that contains nerves and blood vessels.
"We found that odontoblasts, which support tooth shape, are also responsible for detecting cold," says pathologist Jochen Lennerz, MD, PhD, one of the lead authors of the paper and medical director of the Center for Integrated Diagnostics at General Hospital. of Massachusetts. (MGH).
"This research brings a new function to this cell, which is exciting from a basic science point of view. But now we also know how to interfere with this cold-sensing function to inhibit dental pain."
Teeth that hurt from cold exposure can occur for many reasons. Many people have experienced severe cold pain when, for example, they have a hole in a tooth from an untreated socket.
But teeth can also become very sensitive to cold due to gum erosion due to aging. Some cancer patients treated with platinum-based chemotherapies have extreme sensitivity to cold throughout the body. "A breeze on the face registers as extreme pain in the teeth, which can even cause some patients to stop receiving treatment," says Lennerz.
Toothache has been notoriously difficult to study. The hardness of a tooth makes it a difficult tissue to study and inducing tooth pain in humans requires opening the tooth. Therefore, the team of researchers conducted experiments on mice whose molars were drilled under anesthesia.
Mice with dental lesions display pain with their behavior; They drink up to 300% more sugar water than their littermates without dental lesions, for example. In previous research, the team of researchers had discovered TRCP5, a protein encoded by the TRCP5 gene that is expressed in nerves in many parts of the body. Their earlier discovery allowed researchers to focus on TRCP5 as a mediator of cold pain.
By studying genetically altered mice that did not have the TRCP5 gene , the researchers found that mice with injured teeth did not exhibit increased drinking behavior and behaved like mice without dental injuries.
"We now have definitive evidence that the TRCP5 temperature sensor transmits cold through the odontoblast and activates the nerves, creating pain and hypersensitivity to cold," says Lennerz. "This sensitivity to cold may be the body’s way of protecting a damaged tooth from further injury."
Specifically, in response to cold, the TRCP5 protein opens channels in the odontoblast membrane, allowing other molecules, such as calcium, to enter and interact with the cell. If the pulp of the tooth is inflamed from a deep cavity, for example, TRCP5 is overabundant, causing increased electrical signaling through nerves that emerge from the root of the tooth and travel to the brain, where the sensation is perceived. pain.
When gums recede from aging, teeth can become hypersensitive because odontoblasts sense cold in a newly exposed region of the tooth.
"Most cells and tissues slow down their metabolism in the presence of cold, so donor organs are put on ice," says Lennerz. "But TRPC5 makes cells more active in the cold, and the ability of odontoblasts to sense cold through TRPC5 makes this discovery so exciting."
Lennerz confirmed the presence of the TRPCS protein in extracted human teeth, which was a technical tour de force. "Our teeth do not have to be cut into ultra-thin layers in order to study them under the microscope," says Lennerz, who first had to decalcify the teeth and put them in epoxy resin before cutting them and identifying the TRPC5 channels in the odontoblasts.
The research team also identified a drug target to minimize tooth sensitivity to cold. For centuries, clove oil has been used as a remedy for tooth pain. The active agent in clove oil is eugenol , which blocks TRCP5.
Toothpastes containing eugenol are already on the market, but the findings of this study may lead to more powerful applications to treat teeth that are hypersensitive to cold. And there may be novel applications for eugenol, such as systemic treatment of patients with extreme sensitivity to cold due to chemotherapy. "I’m excited to see how other researchers will apply our findings," Lennerz says.
Discussion
Dentin sensitivity as a thermomechanical sensation
This study aimed to find the molecular mechanism of cold detection in teeth. Using a novel jaw and nerve preparation that allowed us to record propagated electrical activity from intact teeth, we identified TRPC5 and TRPA1 as the molecular cold sensors and odontoblasts as the site of cold transduction.
This experimental model allowed us to close an important gap in our understanding of toothache since it is the first model that allows the evaluation of the dental sensory system in its entire anatomical and, necessarily, physiological context in transgenic mice. This is essential because, unlike any other part of the body, functional dental anatomy poses complex problems in detecting harmful physical stimuli.
The location of the odontoblast cell layer in the outermost area of the dental pulp makes it a natural barrier between the mineralized hard tissues and the soft dental pulp. Each odontoblast has a process that protrudes into a dentinal tubule where it is immersed in dentinal fluid. Its body and cell process are surrounded by unmyelinated sensory nerves within the first 100 μm of the odontoblast-predentin border. This unique hierarchical arrangement, from enamel at the macroscale through fluid-filled dentinal microtubules to ion channels at the molecular level, provides the structural basis for thermal pain coding.
In summary , our data elucidate the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. Therefore, cultured neuron models alone are insufficient to capture the functional complexities of dental cold sensing. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold detection.
Under human inflammatory conditions with injured or patent dental pulp, TRPC5 expression is increased in sensory axons.
The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing through the relative sensitivity of TRPC5 to intracellular [Ca2+] and lack of desensitization. TRPM8, in contrast, is downregulated in inflammation and, with its contrasting biophysical properties and location in coronal enamel predentinal odontoblasts, may trigger more transient cold responses or indicate a different function (e.g., As an osmosensor similar to TRPM8 reports in the cornea).
In addition to being an odontoblast cold sensor, TRPC5 can signal prolonged pain and act as an oxidative stress sensor during inflammation.
In this regard, TRPC5 may be an effective target for the treatment of dentin hypersensitivity and inflammatory dental pain. The main ingredient in clove oil (Syzygium aromaticum), eugenol, has been used for centuries as an analgesic in dentistry and inhibits TRPC5 currents.
In the evolutionary arms race between teeth and food, the odontoblast with its elongated process extending beyond the boundary between dentin and enamel satisfies the need for a specialized nociceptor within a tough shell. We propose that odontoblasts alert us to tooth damage from lower temperature extracorporeal objects.
