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

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.

Bone formation: Hormone and growth factor work together

A key hormone and growth factor work together to help turn bone-forming cells into mature bone. Janet Crane and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, tested the effects of parathyroid hormone (PTH) and insulin like-growth factor type 1 (IGF-1) signaling on the differentiation of bone-forming osteoblasts by modulating the activity of their receptors in genetically engineered mice. They found a specific part of the PTH type 1 receptor has a phosphate group added to it by the IGF-1 receptor. This chemical tagging leads to changes in the cytoskeleton of osteoblasts that enhance the formation of mature bone cells known as osteocytes. Mice without this PTH receptor had reduced numbers of osteocytes in their bone. The findings reveal a novel signaling mechanism behind this cellular transition during bone building.

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