Chondrosarcoma: With Updates on Molecular Genetics
Figure 8
(a) Schematic representations of IHH/PTHLH signaling in the growth plate. The growth plate is composed of chondrocytes at different stages of differentiation, finally leading to longitudinal bone growth. This process is tightly regulated by IHH/PTHLH signaling. IHH, expressed by transition zone chondrocytes, diffuses and binds to Patched (Ptc) in the hypertrophic zone, stimulating PTHLH expression. PTHLH then binds to its receptor in the transition zone and upregulates Bcl-2, which inhibits chondrocyte differentiation and downregulates IHH secretion. EXT gene products play a role in the diffusion of hedgehog proteins and FGF-FGFR interaction. Therefore, defect or absence of EXT genes results in an abnormal IHH diffusion pattern, leading to an osteochondroma. (b) Proposed genetic model for peripheral secondary CHS. Analogous to Knudson’s two-hit model, both alleles of an EXT gene are inactivated for osteochondroma formation in both HME and solitary osteochondroma. Genetic instability and reactivation of PTHLH signaling characterizes the malignant transformation of osteochondroma. (c) Proposed genetic model for central secondary CHS. Patients with enchondromatosis infrequently harbor PTHR1 mutation, which disrupts the normal IHH-PTHLH feedback loop, leading to constitutive hedgehog signaling. In most enchondromas, causative genetic or epigenetic changes have not been identified.
