IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition

Tao Qiu,Lingling Xian,Xu Cao,Hui Xie,Liang Xie,Janet L Crane

doi:10.1038/s41413-017-0002-7

Abstract

Parathyroid hormone (PTH) regulates bone remodeling by activating PTH type 1 receptor (PTH1R) in osteoblasts/osteocytes. Insulin-like growth factor type 1 (IGF-1) stimulates mesenchymal stem cell differentiation to osteoblasts. However, little is known about the signaling mechanisms that regulates the osteoblast-to-osteocyte transition. Here we report that PTH and IGF-I synergistically enhance osteoblast-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytoplasmic domain of PTH1R can be phosphorylated by insulin-like growth factor type I receptor (IGF1R) in vitro. Phosphorylated PTH1R localized to the barbed ends of actin filaments and increased actin polymerization during morphological change of osteoblasts into osteocytes. Disruption of the phosphorylation site reduced actin polymerization and dendrite length. Mouse models with conditional ablation of PTH1R in osteoblasts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with complete overlap of PTH1R with phosphorylated-PTH1R positioning in osteocyte dendrites in wild-type mice. Thus, our findings reveal a novel signaling mechanism that enhances osteoblast-to-osteocyte transition by direct phosphorylation of PTH1R by IGF1R.

Highlights

Osteocytes make up over 90% of bone cells and play a major role in control of skeletal tissue homeostasis[1]
Osteoblast and osteocyte differentiation is enhanced by costimulation of Insulinlike growth factor type 1 (IGF-1) and Parathyroid hormone (PTH) IGF-1 is known to play a key role in osteoblast differentiation; little is known about osteoblast-to-osteocyte differentiation
These results suggest that both IGF1 and PTH play a role during osteoblast-to-osteocyte transition, and the role of PTH in osteocytes depends on the presence of insulin-like growth factor type 1 receptor (IGF1R)

Summary

Introduction

Osteocytes make up over 90% of bone cells and play a major role in control of skeletal tissue homeostasis[1]. Osteocytes regulate bone remodeling, maintain phosphate homeostasis, serve as mechanosensors, and secrete endocrine hormones to communicate with other organs[2]. Osteocytes are terminally differentiated osteoblasts derived from mesenchymal stem cells (MSCs) that become embedded in bone matrix. During the differentiation of osteoblasts to osteocytes, the cells undergo morphological changes, transitioning from a polygonal shape into cells with dendritic extensions[3,4]. While signaling mechanisms that direct differentiation of MSCs to osteoblasts have been extensively studied, the characterization of the transition of osteoblasts to osteocytes is just beginning to be elucidated[2], but the mechanism regulating changes in cytoskeletal proteins, enzymes, and hormones remains unclear. As osteocytes can survive for up to decades[2], further studies elucidating factors that influence osteocyte differentiation are essential for understanding disease conditions and therapeutics

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Conclusion