Fig. 9. Interaction of BMP and Ihh signaling. During endochondral ossification Ihh is expressed in the differentiating chondrocytes (red). Ihh induces the expression of PTHrP in periarticular chondrocytes (yellow) independently of BMP signaling. The range of PTHrP signaling keeps chondrocytes in a proliferating state and determines the distance from the joint region at which chondrocytes can undergo hypertrophic differentiation. Ihh in addition regulates the expression of Bmp genes in the perichondrium/periosteum and in part of the proliferating chondrocytes (green). BMP and Ihh signaling together upregulate chondrocyte proliferation, thereby pushing cells out of the range of PTHrP signaling. These chondrocytes are released from the block of differentiation and upregulate Ihh expression upon BMP signaling. BMP signaling furthermore negatively regulates the development of terminally differentiated hypertrophic chondrocytes (blue). By regulating chondrocyte proliferation, Ihh expression and terminal hypertrophic differentiation, BMP signaling integrates the different steps of endochondral ossification.
