The TMJ Association advocates for research that will help TMD patients. That means not only finding new drugs or other treatments to relieve jaw pain and dysfunction; it also means basic research to understand the development of the joint and how its associated nerves and muscles control the jaw’s complex movements. That is why we are pleased to report that a young investigator, Dr. Patricia Purcell, from the Department of Plastic and Oral Surgery, Children’s Hospital Boston/Harvard Medical School, has published papers identifying major genes involved in the formation of the TMJ.
As Dr. Purcell explains, the TMJ consists of several tissues, including the glenoid fossa of the temporal bone, the depression in the skull that holds the rounded head, the condyle, of the mandible, and the soft cartilage disc that serves as a cushion between these bones, along with associated nerves, muscles and tendons. In order for the jaw to function properly, all these components must develop in synchrony and be maintained throughout life. For this to occur, the genes that control the formation and maintenance of these tissues have to be expressed at the correct time and place during pregnancy. As yet, however, the genetic, cellular, and molecular mechanisms involved in the formation of the TMJ are poorly understood.
In an earlier study (Purcell et al. 2009, PNAS 106(43): 18297-302) Dr. Purcell reported on a technique called laser capture microdissection, in which a laser is used to isolate discrete parts of the jaw joint in mouse embryonic tissue, in order to identify which genes are abundant in each location, with the final goal of establishing a “blueprint” of the TMJ. Among major genes they found were members of a family of genes involved in the so-called “hedgehog” signaling pathway, which orchestrates embryonic development by turning other genes off and on. One of these hedgehog signaling genes, Gli2, turned out to be essential for initiating the formation of the TMJ disc. Furthermore, when the researchers blocked all hedgehog activity from cartilage-producing cells, the TMJ disc formed, but failed to separate from the condyle. Without separation the disc could not glide smoothly over the condyle when the jaw is in motion, acting as a shock absorber. Thus, Dr. Purcell and her team established that hedgehog signaling plays a very important role in TMJ disc development, acting at two distinct steps: (1) initiation of disc formation, and (2) separation of the disc from the condyle.
Dr. Purcell has also identified another set of genes present in high numbers at another site in TMJ microdissected mouse embryo samples, (Purcell et al., 2012, J. Dent. Res. 91(4): 387-93). Here the research team demonstrated the importance of Sprouty genes, which function by inhibiting the fibroblast growth factor (Fgf) signaling pathway in the development of the TMJ. Fgfs are proteins that mediate the development, maintenance and repair of many organs, including cartilage and bone. The team found that when two Sprouty genes were inactivated in the developing mouse (in other words, no longer able to inhibit the fibroblast growth factor receptors), the glenoid fossa did not form, while the muscles themselves were greatly enlarged. The increase in muscle size correlated closely with an increased number of muscle-forming cells, suggesting that the genes code for substances that regulate muscle cell proliferation. Remarkably, the mice that developed from these embryos had well-formed condyles and discs, demonstrating for the first time that these structures do not require a complete glenoid fossa for their formation.
Why is this work important for TMD patients? The lack of understanding of the genetic, molecular and cell mechanisms responsible for TMJ formation has hampered advances in the TMJ field. There is still not a standardized set of criteria for the diagnosis of TMD, which are now thought of as a family of disorders with many possible defects contributing to disease onset. Basic research on TMJ development may yield new “biomarkers” that could be used to predict the risk that an individual will develop TMD. As well, an understanding of the genes and molecules important in development might also provide clues to new therapies that could be used for the repair or replacement of a diseased or damaged disc or other elements of the joint.
Dr. Purcell came from Chile to study in the U.S. and received a PhD in Genetics at Harvard Medical School, with work in craniofacial development. Her focus on the TMJ started during her postdoctoral training in Dr. Vicki Rosen’s laboratory at The Forsyth Institute in Boston with a fellowship from the Harvard School of Dental Medicine, and continued as an NIH grantee at Harvard with Dr. Cliff Tabin, a world authority on joint formation. She credits her current institution, Children’s Hospital Boston, for their strong commitment to her research program.