Factors influencing osteogenic differentiation in fibrodysplasia ossificans progressiva

Abstract

Studies were performed in C2C12 cells and lymphoblastoid cell lines (LCLs) from unaffected individuals and patients suffering from a rare genetic condition called fibrodysplasia ossificans progressiva (FOP), a disease of heterotopic bond formation and dysregulated BMP signalling.

C2C12 cells were used to investigate the effect of methylation and HSPGs on osteogenic differentiation. These studies demonstrated that DNA methylation can inhibit BMP-stimulated induction of alkaline phosphatase, a marker of osteogenic differentiation. In addition, removal of HSPG glycosaminoglycan (GAG) side chains reduced expression of alkaline phosphatase following BMP treatment, suggesting that HSPGs promote osteogenic differentiation in C2C12 cells.

Control and FOP LCLs were used to investigate the role of HSPGs in BMP signalling. Total and HSPG-specific GAG chain levels were increased on the surface of FOP cells compared to controls. Removal of the HSPG GAG chains reduced BMP signalling in control LCLs, but had no effect in FOP cells, suggesting that FOP cells are resistant to the modulatory effects of HSPGs. Profiling of all HSPGs demonstrated that glypican 1 and syndecan 4 are the most abundantly expressed on control and FOP LCLs, with increased levels on FOP cells, providing additional GAG binding sites. Downregulation of glypican 1 core patients increased BMP signalling in control and FOP cells, suggesting an inhibitory role in BMP signalling. However, downregulation of syndecan 4 decreased BMP signalling in control cells, but not FOP cells, suggesting that FOP cells are resistant to the stimulatory effects of syndecan 4. The elevated BMP signalling observed in FOP LCLs may be at such a level that the cells are unaffected by HSPGs that promote signalling, but respond to HSPGs that inhibit signalling.

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