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Macrodactyly is a disabling congenital disease characterized by overgrowth of soft tissues and bones, which leads to finger enlargement and joint deformity. The mechanism of bone overgrowth in macrodactyly was rarely understood. In our study bone manifestations of three macrodactyly patients were analyzed by micro-CT.  PIK3CA  mutation was detected by next-generation sequencing (NGS) of a tumor gene-panel. The PI3K/AKT/mTOR pathway activation and target genes were analyzed. The osteogenic potential of macrodactyly-derived bone marrow mesenchymal stem cells (MAC-BMSCs) was compared with polydactyly-derived bone marrow mesenchymal stem cells (PD-BMSCs).  PIK3CA  inhibitors were tested for proliferation and osteogenesis potential of MAC-BMSCs. Activating  PIK3CA  mutations and activation of PI3K/AKT/mTOR pathway were detected in all MAC-BMSCs. MAC-BMSCs had enhanced osteogenesis potential compared with PD-BMSCs.  PIK3CA  knockdown by shRNA or BYL719 treatment significantly reduced osteogenic differentiation capacity of MAC-BMSCs. RNA-Seq and qRT-PCR revealed the upregulation of distal-less homeobox 5 ( DLX5 ) in MAC-BMSCs compared with PD-BMSCs. The osteogenic potential of MAC-BMSCs was inhibited by  DLX5  knockdown, indicating that  DLX5  is a downstream target of  PIK3CA  activation-mediated osteogenesis. This study revealed that osteogenic differentiation in MAC-BMSCs is enhanced by  PIK3CA  activation mutation through PI3K/AKT/mTOR signaling pathway and can be reversed by  PIK3CA  knockdown or drug inhibition.

Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly