Chondrogenic differentiation in the limb bud follows a proximal to distal sequence in developing limb, resulting in cartilage elements only formed by proliferating chondrocytes. When the skeletal pattern is established the cells at specific regions of this cartilaginous primordium exit of the cell cycle, initiating joint formation, and delimiting the boundary of each individual skeletal element. Later in development, the cells in the centre of each skeletal element instead of initiating joint formation, they become pre-hyper-trophic, leading down the path to hypertrophy and eventual ossification. Although, Wnt14 is the first gene reported to have the ability to initiate joint formation, it is not known why proliferating chondrocytes become pre-joint cells or pre-hypertrophic cell during deve-lopment of appendicular skeleton. Recent evidence involves integrin signaling in the decision between two alternative fates by proliferating chondrocytes in the skeletal elements, pre-joint or pre-hypertrophic fate. In this review will summarize our hypothesis on how chondrocyte differentiation and joint formation are coordinated.
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