Prevention of guanylyl cyclase–B dephosphorylation rescues achondroplastic dwarfism

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase–B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B(7E/7E) mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B(7E/7E) mice with FGFR3(G380R/G380R) mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B(7E/7E) mice with FGFR3(WT/WT) mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B(7E/7E)/FGFR3(G380R/G380R) mice were not shorter than those from GC-B(WT/WT)/FGFR3(WT/WT) mice. At 2 weeks of age, male but not female FGFR3(G380R/G380R) mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B(7E/7E) mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3(G380R/G380R) mice with GC-B(7E/7E) mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.