Fig. 9. Proposed model for the action of Wnt5a and Wnt5b in regulating chondrocyte proliferation and differentiation. The morphology of a developing long bone is schematically shown on the left. Molecular interactions in regulating chondrocyte proliferation and differentiation are shown on the right. The major findings of this study are that Zone I and Zone II chondrocytes express p130 and cyclin D1 differentially, and that Wnt5a and Wnt5b regulate multiple transitional steps between different chondrocyte zones. Wnt5a expression is in purple. Wnt5b expression is in light blue. We show that Wnt5a promotes the expression of p130 but inhibits the expression of cyclin D1. Wnt5a may also downregulate Sox9 transcription activity. We propose these are the underlying mechanisms whereby Wnt5a inhibits the transition from Zone I to Zone II, but promotes the transition from Zone II to the prehypertrophic region. Conversely, Wnt5b enhances Sox9 transcription activity and cyclin D1 expression. This promotes Zone II formation but inhibits cell cycle withdrawal and chondrocyte hypertrophy. Thus, Wnt5a and Wnt5b act in parallel pathways to the Ihh and PTHrP negative feedback loop to coordinate chondrocyte proliferation and differentiation. Sox9 and cell cycle regulators may be the common targets.