Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma

Chondrosarcomas are malignant cartilage-forming tumors arising centrally in bone (central chondrosarcoma) or within the cartilaginous cap of osteochon drorna (peripheral chondrosarcoma). For hereditary multiple osteochondromas , two responsible genes, EXT1 and EXT2, have been cloned. Their recently el ucidated role in heparan sulfate biosynthesis and Hedgehog diffusion leads to the hypothesis that EXT inactivation affects fibroblast growth factor (F GF) and Indian Hedgehog (IHh)/parathyroid hormone-related peptide (PTHrP) s ignaling, two important pathways in chondrocyte proliferation and different iation. The expression of PTHrP, PTHrP-receptor, Bcl-2, FGF2, FGFR1, FGFR3, and p21 is investigated by immunohistochemistry in osteochondromas (n = 24 ) and peripheral (n = 29) and central (n = 20) chondrosarcomas. IHh/PTHrP a nd FGF signaling molecules are mostly absent in osteochondromas. Although n o somatic EXT mutations were found in sporadic osteochondromas, the putativ e EXT downstream targets are affected similarly in sporadic and hereditary tumors. In chondrosarcomas, re-expression of FGF2, FGFR1, PTHrP, Bcl-2, and p21 is found. Expression levels increase with increasing histological grad e. Up-regulation of PTHrP and Bcl-2 characterizes malignant transformation of osteochondroma because PTHrP and Bcl-2 expression is significantly highe r in borderline and grade I peripheral chondrosarcomas compared with osteoc hondromas. In contrast, up-regulation of PTHrP and Bcl-2 seems to be a late event in central cartilaginous tumorigenesis because expression is mainly restricted to high-grade central tumors.