Bone Morphogenetic Proteins and bFGF Exert Opposing Regulatory Effects on PTHrP Expression and Inorganic Pyrophosphate Elaboration in Immortalized Murine Endochondral Hypertrophic Chondrocytes (MCT Cells)

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Abstract
A fundamental question in endochondral development is why the expression of parathyroid hormone–related protein (PTHrP), which inhibits chondrocyte maturation and mineralization, becomes attenuated at the stage of chondrocyte hypertrophy. To address this question, we used clonal, phenotypically stable SV40-immortalized murine endochondral chondrocytes that express a growth-arrested hypertrophic phenotype in culture (MCT cells). Addition of individual cytokines to the medium of MCT cells revealed that bone morphogenetic protein (BMP)-6, which commits chondrocytes to hypertrophy, markedly inhibited PTHrP production. This activity was shared by three other osteogenic bone morphogenetic proteins (BMP-2, BMP-4, and BMP-7) and by transforming growth factor β (TGF-β), which all inhibited the level of PTHrP mRNA. In contrast, basic fibroblast growth factor (bFGF), an inhibitor of chondrocyte maturation to hypertrophy, induced PTHrP in MCT cells and antagonized the effects of BMP-2, BMP-4, BMP-6, and BMP-7 and TGF-β on PTHrP expression. Opposing effects of bFGF and BMPs also were exerted on the elaboration of inorganic pyrophosphatase (PPi), which regulates the ability of hypertrophic chondrocytes to mineralize the matrix. Specifically, BMP-2 and BMP-4, but not BMP-6 and BMP-7, shared the ability of TGF-β to induce PPi release, and this activity was inhibited by bFGF in MCT cells. Our results suggest that effects on PTHrP expression could contribute to the ability of BMP-6 to promote chondrocyte maturation. BMPs and bFGF exert opposing effects on more than one function in immortalized hypertrophic chondrocytes. Thus, the normal decrease in bFGF responsiveness that accompanies chondrocyte hypertrophy may function in part by removing the potential for bFGF to induce PTHrP expression and to oppose the effects of BMPs. MCT cells may be useful in further understanding the mechanisms regulating the differentiation and function of hypertrophic chondrocytes.

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