Abstract
BackgroundAs major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma.MethodsGene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis.ResultsThe expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other.ConclusionsThe BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells.
Highlights
As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma
Expression of BMP and transforming growth factor β (TGFβ) ligands and receptors in central chondrosarcoma The expression of genes for BMP and TGFβ ligands and receptors was measured in central chondrosarcoma and normal cartilage samples by quantitative RT-PCR (Figure 1)
While among the ligands analyzed the BMP2, BMP4, BMP6, BMP7, TGFB1 and TGFB2 genes did not show significant differences between chondrosarcomas of different histological grades, TGFB3 was significantly higher expressed in grade III compared to grade I chondrosarcoma (2-fold, p=0.006)
Summary
As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. Conventional central chondrosarcomas are cartilaginous tumors which arise centrally within the medullar cavity of bone They represent 75% of all malignant cartilage tumors. The correlation of the differentiation stage of chondrosarcoma cells to the degree of malignancy of the tumors indicates that signaling pathways that control normal chondrogenesis may have a regulatory function in the progression of these tumors. Bone morphogenic protein (BMP) and transforming growth factor β (TGFβ) signaling is one of the crucial pathways controlling chondrogenic differentiation in the normal growth plate [5]. The activated type I receptors in turn phosphorylate intracellular Smad molecules which translocate in the nucleus and modulate the expression of target genes. In endothelial cells and chondrocytes, the TGFβ/ALK1/Smad signaling axis appears to be favored in presence of the TGFβ co-receptor endoglin, known as CD105 [7,8]
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