Together, these results strongly indicate that the SCX+ cells of the AF connective tissue normally undergo regionally selective differentiation to contribute to intramembranous bone, endochondral bone, and ligament in the PFS, and that the persistent AF in Wnt1-Cre;Fgfr2−/− mice is largely caused by failed differentiation of SCX+ cells into RUNX2+ and SOX9+ skeletogenic cells. Here, RUNX2 is linked to atrial fibrillation.