LIFTING THE LID ON TOOTH ERUPTION
Molecular biologist reveals the role of the dental follicle

A tooth emerges from a bony crypt.

That sounds more like the title of a Tim Burton film than anatomical fact. But for someone suffering the pain of an impacted molar, the medical term may be apt.

“The unerupted tooth is encased in bone,” explains Gary Wise, head of Comparative Biomedical Sciences at the School of Veterinary Medicine. “That’s a rather unique and interesting thing. You have a hard object, the tooth, in turn enclosed in a hard object, the bone.”

But developing inside a bony crypt (or tooth socket) poses a problem: Somehow it has to get out.

“There has to be a hole, if you will, made in the mandible. That’s called the eruption pathway,” notes Wise. And since the mandible is solid bone, “one of the requirements of [tooth] eruption is bone resorption.”

Professor Gary Wise, Head of Comparative Biomedical Sciences, School of Veterinary Medicine. Photo credit: Kevin Duffy

For a molar to emerge, the lid of its crypt must be chipped away and new bone created below to push it into the eruption pathway. This complex feat of bio­engineering requires the precise regulation of the activities of two cell types, known as osteoclasts (bone destroyers) and osteoblasts (bone builders).

Until Wise began to look into it, no one was certain how their role in tooth eruption was regulated. “My work has focused on what is the molecular and cellular basis for this. We’ve come a long way, actually, in answering that.”

Wise, a cell biologist, began studying tooth eruption in the early 1980s with colleague Don Cahill at the University of Miami. Cahill, along with researcher Sandy Marks, was the first to link tooth eruption with a tiny sac of connective tissue known as the dental follicle. Almost invisible to the naked eye, the follicle surrounds the tiny tooth bud. Remove it, and no tooth will erupt.

Intrigued by that mystery, Wise reset the course of his career to find out why.

The dental follicle proved full of surprises. “Basically, it synthesizes molecules at a given time that will recruit osteoclast precursors to the follicle.” These precursor cells then fuse in a process called osteoclastogenesis, and the resulting osteoclasts resorb the bone to form the eruption pathway.

Wise chose the rat first mandibular molar as his research model, which, like the human molar, is a tooth of limited eruption. It grows to a certain point, then stops.

In the eruption of rat mandibular molars, the dental follicle produces its first series of osteoclast forming molecules on day three after birth. These include monocyte chemotactic protein 1 (MCP-1), colony stimulating factor 1 (CSF-1) and a molecule known as RANKL. A second burst of osteoclast formation comes around day ten in the life of the rat, leading to the eventual eruption of the first mandibular molar on day eighteen.

While serving up its brew of bone destroying agents, the dental follicle also prepares a kind of antidote, known as osteoprotegrin (or OPG), which inhibits the destruction of bone. By carefully regulating these countervailing agents, the dental follicle drills the eruption pathway without risking the integrity of surrounding bone.

Yet that’s just half its job. The same tiny sac that oversees bone resorption above the tooth simultaneously directs the growth of new bone beneath it. The process is similar, except that the molecules synthesized in the follicle beneath the rising tooth (primarily bone morphogenetic protein 2, or BMP-2) promote the development of osteoblasts, the bone building molecules.

Thus the regulation of alveolar bone resorption is both chronological and spatial, said Wise. It's chronological because the genes for bone resorption and formation must either be up regulated or down regulated in the follicle at a specific time. It's spatial in that genes promoting bone resorption tend to be expressed in the upper half of the follicle, while genes promoting bone growth are expressed more in the basal half.

The job is done when a new molar pierces the gingiva and assumes its duties as a tooth. At that point, the dental follicle morphs into a periodontal ligament—its final trick—anchoring the tooth it once raised from the crypt.

Wise suspects his research may assist in the treatment of impacted third molars and periodontitis, two diseases that together represent annual health care costs in the billions of dollars. In recognition of its import, Wise’s study of the molecular aspects of tooth eruption has been continuously supported by the National Institutes for Health since 1991.

...from the Autumn 2007 Issue