Pro-fibrotic effects of PFKFB4-mediated glycolytic reprogramming in fibrous dysplasia.

Fibrous dysplasia (FD) caused by a mosaic somatic mutation of GNAS is characterized by replacement of the affected bone with abnormal fibrous tissue. Herein, we present novel disease models for FD developed with pairs of isogenic wild-type and GNAS(R201H)-mutated induced pluripotent stem cells (iPSCs) and their derivative mesenchymal stem cells (MSCs). Both 2D and 3D MSC culture models for FD successfully reflect FD's typical molecular characteristics, such as enhanced cAMP level, PKA activity, CREB1 phosphorylation and the pathologic fibrotic phenotype. The fibrotic features of GNAS(R201H) FD model cells were closely linked to augmented glycolysis and depended on glycolytic PFKFB4 and the activation of pro-fibrotic TGFβ signalling. Either depletion of PFKFB4 or inhibition of glycolysis or TGFβ signalling potentially blocked fibrosis progression in GNAS(R201H) FD model cells. Our FD models could facilitate a better mechanistic understanding of FD and help develop effective therapeutics for FD and other fibrosis diseases.