Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor.

Leia C Shuhaibar,Jerid W Robinson,Robert Feil,Tracy F Uliasz,Siu-Pok Yee,Melanie C Fisher,Jeremy R Egbert,Lincoln R Potter,Laurinda A Jaffe,Giulia Vigone,Deborah Kaback,Caroline N Dealy,Valentina Baena,Ninna P Shuhaibar

doi:10.7554/elife.31343

Abstract

Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP production in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. The dephosphorylation requires a PPP-family phosphatase. Thus FGF signaling lowers cyclic GMP production in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.

Highlights

Longitudinal growth of limbs and vertebrae depends on division and differentiation of chondrocytes within the cartilage growth plates located at each end of the growing bone, resulting in formation of a scaffold that is subsequently mineralized (Kozhemyakina et al, 2015)
We found that fibroblast growth factor (FGF)-induced dephosphorylation and inactivation of natriuretic peptide receptor 2 (NPR2) decreases cGMP production in growth plate chondrocytes, contributing to FGFdependent decreases in bone growth
The increases in body and bone length, which resulted from an inability of NPR2 to be inactivated by dephosphorylation, phenocopied those previously reported for mice in which NPR2 activity was increased by overexpression of the NPR2 agonist C-type natriuretic peptide (CNP) or by an activating mutation in the NPR2 guanylyl cyclase domain (Yasoda et al, 2004; Miura et al, 2012) and in a human patient with the same activating mutation in NPR2, who was 14% taller than average at 15 years of age (Miura et al, 2012)

Summary

Introduction

Longitudinal growth of limbs and vertebrae depends on division and differentiation of chondrocytes within the cartilage growth plates located at each end of the growing bone (see Figure 2B), resulting in formation of a scaffold that is subsequently mineralized (Kozhemyakina et al, 2015). These processes are tightly controlled by multiple regulatory pathways.

Methods

Results

Conclusion