In several tissues, hyaline cartilage persists throughout life and serves structural and biomechani-cartilaginous templates are eventually invaded by blood vessels before they are remodeled into trabecular bone.
At the cartilaginous stages, the cells transit through an ordered sequence of proliferation and late differentiation steps, culminating in chondrocyte hypertrophy and matrix mineralization. In this process, the extracellular matrix is extensively remodeled! which results from the activation of stage-specific genes (Cancedda et al., 1995). Aggrecan and collagens II and IX are expressed
throughout, albeit at different levels. By contrast, collagen VI and matrilin-1 (cartilage matrix protein, CMP) are markers of early and late proliferative stages, respectively (Quarto et al., 1993; Chen et al., 1995;Muratoglu et al., 1995; Szüts et al., 1998).

Collagen X and alkaline phos-phatase are characteristic products of hypertrophic chondrocytes (Schmid and Conrad, 1982).

Chondrocyte maturation requires extracellular stimuli that include thyroid hormones and insulin, or insulinlike growth factors. However, it is now established that there are also powerful negative control elements (Kato and Iwamoto, 1990; Tschan et al., 1993; Böhme et al., 1995; Colvin et al., 1996; Deng et al., 1996; Vortkamp et al., 1996) that either delay or entirely repress
endochondral ossification. In the cranial section of chick embryonic sterna (Böhme et al., 1995) or articular cartilage (D’Angelo and Pacifici, 1997), late chondrocyte differentiation proceeds spontaneously unless prevented at early or late proliferative stages by soluble and/or stationary environmental factors that interfere at distinct checkpoints of the maturation cascade (Vortkamp et al., 1996; Szüts et al., 1998; Pathiet al., 1999). This complexity is required to achieve appropriate progression rates and final extents of chondrocyte maturity. For example, severe skeletal abnormalities are the consequences of gain- or loss-offunction mutations in genesontrolling chondrocyte proliferation and differentiation. Such genes include those of fibroblast growth factors and their receptors (Rousseau et al., 1994; Neilson and Friesel, 1995;
Colvin et al., 1996; Deng et al., 1996; Burke et al., 1998).During adolescence, human ribs contain two cartilaginous regions, i.e. costal cartilage joining ribs to the sternum, and costal growth plates responsible for the longitudinal growth of the ribs. The two cartilaginous regions are separated from each other by bone tissue.

Costal cartilage undergoes incomplete ossification, which is not initiated before the onset of puberty. In addition, the process is very slow in comparison with bone formation during development or in growth plates, including the costal growth plate. Unlike articular cartilage, rib cartilage is vascularized immediately after birth but, nevertheless, is not mineralized before early
adulthood. Thus, the tissue is a permanent hyaline cartilage, in which endochondral ossification cal functions. For example, joint cartilage permanently conditions the surface of long bones to permit loadbearing and smooth articulation. Costal cartilage flexibly joins the bony part of the ribs to the sternum, and cartilaginous rings maintain the lumen of the trachea, while providing essential elasticity.

In skeletal elements undergoing endochondral ossification, however, hyaline cartilage is a transient tissue. During development, growth, and repair of bones, avascular is arrested only after chondrocyte differentiation has advanced to very late stages. This study was undertaken
to define the checkpoint of this negative control and to identify extracellular signals required to overcome the differentiation barrier. We have studied the occurrence of cartilage maturation markers and mineral deposition in situ and have investigated the capacity of costal chondrocytes to express a fully hypertrophic phenotype in vitro.

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