Fig. 7. Proposed model for the regulation of chondrocyte differentiation by PPR and Ihh signaling. (A) PPR signaling in the columnar chondrocytes blocks terminal differentiation (arrow 2). PPR signaling in chondrocytes also negatively controls the differentiation of periarticular chondrocytes to columnar chondrocytes (arrow 1). (B) Application of the model to mice with PPR mutations. Acceleration of cell supply to the columnar region at step 1 in Ppr^d/– leads to an increase in hypertrophic cell production because of the partial restoration of a cell amplification step in the columnar layer. Acceleration of step 1 in Ppr^–/– compensates for the loss of the cell amplification system in the columnar layer. Ihh activity in the periarticular region negatively correlates with PPR signaling in these models. (C) Integrated model of PTHrP/Ihh feedback loop. PTHrP signaling directly blocks premature hypertrophic differentiation (a). Ihh positively regulates PTHrP expression in the periarticular region (b). In the presence of PTHrP, chondrocytes form columns between the periarticular region and the Ihh-expressing domain (c). Ihh action probably stimulates early chondrocyte differentiation to increase chondrocyte population with higher proliferation rate (d).