Genetic Influences on Temporomandibular Joint Development and Growth

Abstract

The temporomandibular joint (TMJ) is a small synovial joint at which the mandible articulates with the skull during movements involved in speaking and mastication. However, the secondary cartilage lining its joint surfaces is indicative of a very different developmental history than limb cartilages. This review summarizes our current knowledge of genes that regulate the formation of primary components of the TMJ, as well as genes that regulate postnatal growth of the TMJ. Although the TMJ is regulated by some of the same genes that are important in limb joints, others appear unique to the TMJ or have different actions. Runx2, Sox9, and members of the TGF-β/BMP family are critical drivers of chondrogenesis during condylar cartilage morphogenesis, and Indian hedgehog (Ihh) is important for formation of the articular disc and cavitation. Osterix (Osx) is a critical regulator of endochondral bone formation during postnatal TMJ growth.

Introduction

For many years, the temporomandibular joint (TMJ) has been a misunderstood joint. Thought by many in the 1920 to the 1940s to be a nonloaded joint (Robinson, 1946, Wilson, 1920), it is now generally agreed that significant loads are delivered to the TMJ as a consequence of mastication and incision (Hylander, 1986, Iwasaki et al., 2010). As a synovial joint with an articular disc, the TMJ was long presumed to be a smaller version of the knee or hip joint by cartilage researchers in the orthopedic community and therefore mostly ignored. It is only relatively recently that this small joint has become of interest to those outside dental and craniofacial research. Over the last 20–30 years, the implications of its unusual morphogenesis have driven investigations into the molecular and cell biology of the TMJ. However, it is only in the last decade that specific genes that are important for TMJ development and growth have been identified using transgenic mouse models.

Building on the early work of Hall (1972), the TMJ has long been understood to be a joint comprised of secondary cartilage (Beresford, 1981), a tissue that differs in several ways from the primary cartilages that are present in the developing limb joints and cranial base. It is designated as secondary because the cartilage capping the mandibular condyle (mandibular condylar cartilage or MCC) develops after the bone of the mandibular ramus, the opposite of the “cartilage first, then bone” sequence that characterizes primary cartilages. As a result of this developmental hierarchy, the primary cartilaginous joints of the limbs are often mostly formed by the time that the MCC and other intraarticular joint structures of the TMJ are beginning to form. The MCC develops adjacent to the intramembranous bone of the mandible, distinct from Meckel's cartilage (Radlanski et al., 2003, Vinkka, 1982), arising either from alkaline phosphatase (AP)-positive cells of likely periosteal origin (Shibata, Fukada, Suzuki, Ogawa, & Yamashita, 2002) or as a condensation separate from the developing bone (Anthwal et al., 2008, Vinkka, 1982). The MCC is only one of many secondary cartilages that are found, transiently in some instances, at many locations in the developing craniofacial complex (Vinkka, 1982). Secondary cartilages continue postnatally in regions such as the mandibular condyle, angular process of the mandible, and intermaxillary suture (Hinton, 1988, Petrovic, 1972). Because of its persistence and role in the growth of the mandible in height and length, the MCC is one of the most important secondary cartilages. Another oddity of the TMJ is that it is a purely mammalian joint; it does not exist in reptiles, but develops in mammals in conjunction with the loads produced by a specialized dentition. Thus, the periosteum of formerly intramembranous bones was transformed into a perichondrium in force-bearing areas where the “new” TMJ would develop (Crompton, 1985). This evolutionary transition is reflected in the formation of the TMJ by three separate mesenchymal condensations (condylar, temporal, and disc) that grow toward each other during development (Sperber, 2001), as compared to the single block of mesenchyme within which the joints involving primary cartilaginous articulations develop.

At least three important differences delineate the secondary cartilage at the MCC from primary cartilages of the limbs and cranial base. First, the cells that proliferate in the MCC are not differentiated chondrocytes, but rather only partially differentiated along the chondrogenic pathway—i.e., “prechondroblasts” that are polymorphic in shape rather that rounded like chondrocytes and that secrete type I collagen rather than type II collagen that is characteristic of the underlying chondrocytes (Mizoguchi et al., 1990, Silbermann et al., 1987). A relatively hypocellular fibroblastic layer (the articular layer) overlies the prechondroblastic layer, and together they comprise the perichondrium that surmounts the cartilage proper of the MCC (Fig. 1). In keeping with its origins adjacent to the periosteum of the ramus of the intramembranous mandible, the articular and prechondroblastic layers of the MCC perichondrium are contiguous with the fibrous and osteogenic layers of the ramus periosteum. Second, the MCC, like other secondary cartilages (Fig. 2) but unlike primary cartilages, can be transient in its expression, requiring conditions of low oxygen tension and/or function to maintain its cartilaginous phenotype. Because the MCC developed in mammals via the localized transformation of a periosteum to a perichondrium in a region (the “new” TMJ) subjected to biomechanical forces, the MCC can diminish in size or be replaced by bone if the evoking stimulus is reduced (Bouvier & Hylander, 1984; Hinton, 1988) or eliminated by lack of movement (Carlson et al., 1980, Glineberg et al., 1982) or placement in a nonfunctional environment (Duterloo and Wolters, 1971, Engelsma et al., 1980, Petrovic et al., 1975). Last, the MCC acts as a site of growth for the mandible to increase in length and height during prenatal and early postnatal life, and also as an articular cartilage beginning with the ingestion of hard food. Thus, it subsumes the functions of both the growth plate and articular cartilage, but in a single tissue that never develops an epiphysis.

Given its unusual manner of development and the distinctive characteristics of its dividing cells, it would not be surprising if the molecular determinants of development and growth of the MCC and TMJ were somewhat different from those in primary cartilaginous joints. The goal of this chapter is to summarize what is known to date of the genetic regulation of TMJ development and growth. It is a “snapshot” to be sure, but appreciation of the state of our knowledge can facilitate comparisons with limb joints and identify areas for future study.