Up-Regulation of PTHrP and Bcl-2 Expression Characterizes the Progression of Osteochondroma towards Peripheral Chondrosarcoma and Is a Late Event in Central Chondrosarcoma

Abstract

SUMMARY:Chondrosarcomas are malignant cartilage-forming tumors arising centrally in bone (central chondrosarcoma) or within the cartilaginous cap of osteochondroma (peripheral chondrosarcoma). For hereditary multiple osteochondromas, two responsible genes, EXT1 and EXT2, have been cloned. Their recently elucidated role in heparan sulfate biosynthesis and Hedgehog diffusion leads to the hypothesis that EXT inactivation affects fibroblast growth factor (FGF) and Indian Hedgehog (IHh)/parathyroid hormone-related peptide (PTHrP) signaling, two important pathways in chondrocyte proliferation and differentiation. The expression of PTHrP, PTHrP-receptor, Bcl-2, FGF2, FGFR1, FGFR3, and p21 is investigated by immunohistochemistry in osteochondromas (n ϭ 24) and peripheral (n ϭ 29) and central (n ϭ 20) chondrosarcomas. IHh/PTHrP and FGF signaling molecules are mostly absent in osteochondromas. Although no somatic EXT mutations were found in sporadic osteochondromas, the putative 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 grade. Up-regulation of PTHrP and Bcl-2 characterizes malignant transformation of osteochondroma because PTHrP and Bcl-2 expression is significantly higher in borderline and grade I peripheral chondrosarcomas compared with osteochondromas. 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. (Lab Invest 2000, 80:1925-1933.

Functional characterization of osteosarcoma cell lines provides representative models to study the human disease

“…31 Next to the H&E, Periodic acid-Schiff and Masson's trichrome stainings to assay the histology of the xenografts, the slides were stained with all antibodies listed in Table 3, which also summarizes the IHC conditions. All stainings in this study were independently evaluated by two pathologists (IM and ALLB) as previously described in detail.…”

The role of noncartilage‐specific molecules in differentiation of cartilaginous tumors

“…4 Antigen retrieval was performed by boiling tissue sections in citrate buffer, pH 6.0, in a microwave oven for 10 seconds. Sections from CB and CMF series were then incubated overnight with anticathepsin K 17,18 It has been demonstrated that this scoring system is highly reproducible on decalcified bone tumor specimens. 4,18 The cellular localization (nuclear, cytoplasmic, and membranous) of immunopositivity was also noted.…”

“…Sections from CB and CMF series were then incubated overnight with anticathepsin K 17,18 It has been demonstrated that this scoring system is highly reproducible on decalcified bone tumor specimens. 4,18 The cellular localization (nuclear, cytoplasmic, and membranous) of immunopositivity was also noted. Scores that were generated with the same evaluation system for p16INK4A and cyclin D1 (CCND1) in CMF and HGCCS were available from previous studies.…”

Cell biology of osteochondromas: Bone morphogenic protein signalling and heparan sulphates

“…Skeletal deformities can lead to functional problems and morbidity due to the entrapment of blood vessels, nerves and tendons. The possibility of transformation into a low-grade chondrosarcoma increases to 5 % in MHE [4]. While the disease can occur spontaneously, it has been estimated that 80 % of affected individuals have a positive family history with varied penetrance among affected members [28,34].…”