Wnt 5 a and Wnt 5 b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation

One of the major processes of vertebrate skeletal development is endochondral bone formation, in which mesenchymal cells first condense and then differentiate into chondrocytes to form the cartilaginous shaft of the future bone. In the developing cartilage, proliferative chondrocytes differentiate to form first prehypertrophic and then hypertrophic chondrocytes (Cancedda et al., 1995; Linsenmayer et al., 1991; Vortkamp et al., 1996). This process is tightly regulated, which ensures proper longitudinal growth of long bones (Hunziker, 1994). As a result, specific spatial zones of chondrocytes with distinct patterns of proliferation, differentiation and cell morphology are laid down along the longitudinal axis of a developing long bone. It has been shown that the proliferative and articular/resting chondrocyte region can be further divided into two zones (Zone I and Zone II) based on the distinct cell morphologies, developmental fates and functions (Abad et al., 2002; Iwamoto et al., 2000). Zone I corresponds to the epiphysis of developing long bones. Zone I cells are round and divide less frequently (Kobayashi et al., 2002; Long et al., 2001). They are articular chondrocytes that will become permanent articular cartilage and resting chondrocytes in the growth plate (Archer et al., 1994; Hunziker, 1994; Mitrovic et al., 1978; Pacifici, 1995). Articular cartilage maintains normal joint function throughout life, whereas resting chondrocytes may contain cells similar to stem cells that are capable of generating new clones of proliferative zone chondrocytes (Abad et al., 2002). Zone II cells are highly proliferative chondrocytes in the growth plate that will exit the cell cycle and undergo hypertrophy (Howlett, 1979; Hunziker, 1994; Karp et al., 2000). Zone II cells are flattened and increase their cell size gradually the closer they are to the hypertrophic zone. These cells divide more frequently and line up with each other to form columns parallel to the long axis of the bone (Dodds, 1930; Long et al., 2001). Zone II depends on Zone I for a constant supply of proliferative chondrocytes. In the meantime, a population of undifferentiated chondrocytes remains in Zone I to maintain joint function at all times. Thus, the transition between Zone I and Zone II has to be carefully regulated. However, the underlying molecular mechanism is still poorly understood. Signaling molecules have been shown to play important roles in regulating chondrocyte proliferation and differentiation (reviewed by de Crombrugghe et al., 2001; Karsenty, 2001). Disruption of the normal cell signaling during endochondral bone formation results in skeletal anomalies in both humans and mouse mutants (Gao et al., 2001; Li and Olsen, 1997). Indian hedgehog (Ihh) and parathyroid hormone related peptide (PTHrP; Pthlh – Mouse Genome Informatics) are two signaling molecules that play crucial roles in regulating the pace of chondrocyte hypertrophy through forming a negative feedback loop (Lanske et al., 1996; Vortkamp et al., 1996). 1003 Development 130, 1003-1015 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00324