Figure 3

Growth plate signaling in the normal growth plate. Indian Hedgehog protein (IHh) is expressed in the prehypertrophic cells, and diffuses over a variable distance to its receptor Patched (PTCH). Subsequently, increased secretion of ParaThyroid Hormone Like Hormone (PTHLH) is induced at the apical perichondrium via an incompletely understood mechanism. PTHLH then diffuses to its receptor, whose expression is restricted to the late proliferating chondrocytes, inhibiting their further differentiation, resulting in less IHh producing cells, which closes the feedback loop. Thus, PTHLH regulates the pace of chondrocyte differentiation by delaying the progression of chondrocytes towards the hypertrophic zone, allowing longitudinal bone growth. Defective or absent EXT proteins leading to altered or absent HSPG expression at the cell surface may affect this negative feedback loop by disturbing the diffusion of IHh, produced at the pre-hypertrophic chondrocytes, towards its receptor Ptc.