Chapter Four - Genetic Influences on Temporomandibular Joint Development and 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.
Section snippets
Normal Morphogenesis and Cell Biology of the TMJ
In order to evaluate the TMJ phenotypes in transgenic mice models, an appreciation of the normal development of the murine TMJ (Fig. 3) is necessary. Joint formation commences with the appearance of mesenchymal condensations that will become the condyle and mandibular fossa, with a third condensation between them that will become the articular disc (E13.5). Next, chondrocytes differentiate in the deeper layers of the MCC (E15.0), and bone formation becomes evident in the mandibular fossa. At
Agenesis of Mandibular Condylar Cartilage
Inactivation of either Runx2 or Sox 9, which are both expressed in the mesenchymal condensation that initiates the formation of the mandibular condyle and later expressed in the prechondroblastic zone, has been shown to result in agenesis of the condylar cartilage. Because Runx2 is necessary for bone formation, mice-lacking Runx2 do not form bone at all. Curiously, while Runx2(−/−) mice exhibited no disruption of primary cartilage formation (e.g., in the limbs and Meckel's cartilage), the MCC
Agenesis or Abbreviation
Less is known of the genetic effects on development of the mandibular fossa and articular disc because the focus is often on the condylar cartilage and the other structures are either unreported or not imaged. However, in studies where mandibular fossa status is reported, condylar cartilage agenesis is typically associated with agenesis or significant reduction in the mandibular fossa. Disrupted disc morphogenesis, often accompanied by dysfunctional development of joint cavities, is another
Disc Agenesis and Lack of Joint Cavity Formation
The articular disc develops from a third mesenchymal condensation interposed between the condensations that will become the MCC and the mandibular fossa. A condensation of cells in this intermediate region is discernible by E16.5, and gradually assumes the shape of a disc. Simultaneously, small clefts in the mesenchyme appear between the forming disc and the temporal bone. The initial coalescence of these clefts forms the superior joint cavity (space); the inferior joint space between the disc
Discussion
Although more detailed studies on existing genes and additional genetic models are needed, some broad conclusions can be drawn based on our current knowledge. Clearly, certain genes are critical for the specification of a chondrogenic path for the MCC prechondroblastic cells. In mice lacking Runx2, Sox9, BMPr1a, and TGFBr2, the condylar cartilage never forms or forms in highly abbreviated fashion. Although not examined in all instances, the temporal component of the TMJ fails to form or
Acknowledgments
I am greatly appreciative of the willingness of Drs. Eiki Koyama, Makoto Abe, and Jerry Feng to allow me to use images from their work in this review. The research performed in Dr. Hinton's lab was supported by National Institutes of Health (NIH) grant DE015401. The work performed in Dr. Feng's lab was supported by his NIH grants DE018486 and R56DE022789.
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2021, BoneCitation Excerpt :Similarly, the prechondroblastic layer was demonstrated in rabbit (Fig. S3A) and human cadaver TMJ condyles (Fig. S3B) in a corresponding style as shown in mice, indicating a progressive transition from fibroblasts to chondrocytes via a prechondroblast step is likely a universal event in other species. One of the most unique features of the TMJ condyle is its prechondroblastic layer, which is between the fibrous and chondrocyte layers (Fig. S2A) and expresses both cartilage and bone markers [53,54]. The representative TEM image (Fig. 1A) of the TMJ condyle from a 3-week old mouse exhibited a distinctive ultrastructural feature of the prechondroblast compared with the fibroblast (flat with dendrites) and chondrocyte (round and surrounded by lacunae) as below: 1) irregular cell shape with prominent dendrites, the size of which gradually reduced during postnatal growth; 2) rich collagen fibers either in fibril bundles (yellow dashed circles) or loosely distributed format in ECMs, which gradually disappeared in the cartilage layer; 3) active cell proliferation as indicated by red dashed circles; and 4) lack of lacunae (white dashed circles), which were gradually formed along with chondrogenesis (Fig. 1A–B).
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2020, Archives of Oral BiologyCitation Excerpt :The precision of the movement is imperative for avoiding harm to the stomatognathic system and for amplifying efficiency but also for stimulating growing of craniofacial structures. The load generated by mastication effects the maxillary bones growth maintaining the patency and viscoelasticity of the cranial sutures during aging (Sun, Lee, & Herring, 2007; Herring, 2008; Rice, 2008; Sun, Lee, & Herring, 2004) and the mandibular growth acting on the development of the condyle and changes in the thickness of the cartilage (Hinton, 2014; Hinton, Jing, & Feng, 2015; Ishida, Yabushita, & Ono, 2013; Radke, Kull, & Sethi, 2014). Further mastication seems to have considerable effects on general health problems in adults such as dementia (Tada & Miura, 2017) and obesity (Tada & Miura, 2018) and during developmental age such as impaired spatial memory and learning function (Fukushima-Nakayama’, Ono, & Hayashi, 2017; Hirano et al., 2013; Masood, Masood, & Newton, 2014).
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2020, Oral and Maxillofacial Surgery Clinics of North AmericaCitation Excerpt :Unique structural features make the TMJ and growing mandible particularly vulnerable to TMJ inflammation and mechanical loading. This vulnerability originates from the unique developmental, anatomic, and histologic properties of the TMJ compared with other synovial joints: the intra-articular location of the condylar growth site, the condylar cartilage type (fibrocartilage), the ossification process (endochondral), the cellular organization of the condylar cartilage, the matrix composition, the multidirectional condylar growth capacity, the unique cartilage response to altered TMJ function, and the late cartilage maturation.18–21 The pathologic mechanism of arthritis-induced dentofacial deformity is still not fully understood.
Temporomandibular Joint Condyle–Disc Morphometric Sexual Dimorphisms Independent of Skull Scaling
2019, Journal of Oral and Maxillofacial Surgery