Members of the transforming growth factor beta (TGFfamily users their receptors extracellular modulators and intracellular transducers have been described and these usually impact the development of the cartilaginous skeleton. skeleton. Furthermore genome-wide association studies have linked components of the (TGFsignaling in developing growth plate and articular cartilage as well as the different modes of crosstalk between canonical and noncanonical TGFsignaling. These new insights into TGFsignaling in cartilage may open new potential customers for therapies that maintain healthy articular cartilage. ENDOCHONDRAL BONE FORMATION The skeleton is composed primarily of cartilage and bone. Throughout the axial and appendicular skeleton with the exception of the skull the skeleton is usually created from a hyaline cartilage template. During development cells from three unique lineages (sclerotome paraxial mesoderm and neural crest) undergo chondrogenesis through a similar sequence of events to form the cartilage of the embryonic skeleton (Long and Ornitz 2013 Pitsillides and Beier 2011 (Fig. 1). The first overt sign of chondrogenesis is usually aggregation of mesenchymal chondroprogenitor cells into condensations. This process is usually mediated by elevated expression of various cell adhesion molecules such as neural cadherin (N-cadherin) and neural cell adhesion PF 573228 molecule (NCAM). These molecules mediate crucial cell-cell interactions and are critical for maintenance of the expression of Rabbit Polyclonal to EIF5B. Sox9 the transcription factor currently known to take action earliest in the chondrogenic program (Akiyama and Lefebvre 2011 FIGURE 1 Process of endochondral bone formation and TGFβs role during cartilage development. (A) Mesenchymal progenitor cells condense. (B) Cells of condensations become chondrocytes that synthesize a collagen II and aggrecan-rich extracellular matrix … GROWTH PLATE CARTILAGE FORMATION Cells at the core of the condensations differentiate into PF 573228 PF 573228 chondrocytes. This involves a change in morphology from fibroblast-like to more spherical along with a significant increase in synthesis of specific extracellular matrix (ECM) molecules. The Sox9 mediated transcriptional program continues with the collaboration of the structurally related transcription factors Sox5 and 6 driving the expression of collagen types II IX and XI and the major proteoglycan of cartilage aggrecan (Karsenty et al. 2009 Kronenberg 2003 Long and Ornitz 2013 Cells at the periphery of the condensations retain a fibroblastic morphology and continue to express type I collagen giving rise to the structure known as the perichondrium (for review observe Karsenty and Kronenberg 2009 Chondrocytes in the cores of the condensations in PF 573228 the beginning undergo rapid proliferation PF 573228 that leads to linear growth of the developing skeletal element. Subsequently chondrocytes in the centers of the elements exit the cell cycle and execute a well-coordinated program of maturation. This ordered process of proliferation and differentiation prospects to the formation of stratified zones of cells at different stages of the cell cycle with continued expression of Sox9 throughout the resting and proliferating chondrocytes. PF 573228 From your ends of the element to the center these zones include a layer of relatively quiescent cells (resting zone) that exhibit a round cell morphology a zone of rapidly proliferating cells that have a more flattened morphology and form stacks (columnar or proliferative zone) a zone of postmitotic cells that begin to enlarge and are characterized by the expression of ((prehypertrophic zone) and a zone of terminal enlarged chondrocytes (hypertrophic zone). Most of these undergo cell death leaving an ECM that is replaced by bone-forming osteoblasts (Shapiro et al. 2005 Hypertrophic chondrocytes produce a unique mineralized ECM made up of type X collagen. These cells also produce matrix metalloproteinase 13 (MMP-13) which modifies the ECM to facilitate vascular invasion. The invading vasculature permits the access of osteoprogenitors which differentiate into osteoblasts. These cells build the bone matrix and subsequently replace the cartilage. ARTICULAR CARTILAGE FORMATION AND MAINTENANCE Unlike growth plate cartilage which is usually eventually replaced by bone in most species articular cartilages are permanent structures. Articular cartilage is usually created during embryonic stages at sites of joint formation but is not replaced by bone and instead remains and evolves during postnatal stages of growth (Chan et al. 2012 Articular cartilage is usually distinct from growth plate cartilage in terms of ECM content cellular organization and mechanical.