Incretin accelerates platelet-derived growth factor-BB-induced osteoblast migration via protein kinase A: The upregulation of p38 MAP kinase

Tetsu Kawabata,Takanobu Otsuka,Go Sakai,Gen Kuroyanagi,Akira Mizoguchi,Shujie Wang,Ken-Ichiro Yata,Rie Matsushima-Nishiwaki,Kazuhiko Fujita,Woo Kim,Haruhiko Tokuda,Hiroki Iida,Osamu Kozawa

doi:10.1038/s41598-020-59392-7

Abstract

Incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), secreted from enteroendocrine cells after food ingestion, are currently recognized to regulate glucose metabolism through insulin secretion. We previously demonstrated that platelet-derived growth factor-BB (PDGF-BB) induces the migration of osteoblast-like MC3T3-E1 cells through mitogen-activated protein (MAP) kinases, including p38 MAP kinase. In the present study, we investigated whether or not incretins affect the osteoblast migration. The PDGF-BB-induced cell migration was significantly reinforced by GLP-1, GIP or cAMP analogues in MC3T3-E1 cells and normal human osteoblasts. The upregulated migration by GLP-1 or cAMP analogues was suppressed by H89, an inhibitor of protein kinase A. The amplification by GLP-1 of migration induced by PDGF-BB was almost completely reduced by SB203580, a p38 MAP kinase inhibitor in MC3T3-E1 cells and normal human osteoblasts. In addition, GIP markedly strengthened the PDGF-BB-induced phosphorylation of p38 MAP kinase. Exendin-4, a GLP-1 analogue, induced Rho A expression and its translocation from cytoplasm to plasma membranes in osteoblasts at the epiphyseal lines of developing mouse femurs in vivo. These results strongly suggest that incretins accelerates the PDGF-BB-induced migration of osteoblasts via protein kinase A, and the up-regulation of p38 MAP kinase is involved in this acceleration. Our findings may highlight the novel potential of incretins to bone physiology and therapeutic strategy against bone repair.

Highlights

Bone metabolism is tightly controlled by osteoblasts and osteoclasts[1,2]
We demonstrated that the activation of p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) are involved in the migration of osteoblast-like MC3T3-E1 cells stimulated by platelet-derived growth factor (PDGF)-BB11,12
We demonstrated that incretin amplifies the platelet-derived growth factor-BB (PDGF-BB)-induced migration of these cells via protein kinase A and that this amplification was mediated via p38 MAP kinase activation at least in part

Summary

Introduction

Bone metabolism is tightly controlled by osteoblasts and osteoclasts[1,2] The former cells are responsible for bone formation and the latter for bone resorption. The migration of osteoblasts to sites of resorption by osteoclasts is recognized critical for many physiologically essential processes in www.nature.com/scientificreports bone metabolism, such as the responses to load and remodeling[1,3,4]. The osteoblast migration importantly participates in the pathological processes including fracture repair and metastasis of tumor[5]. Various humoral factors, such as platelet-derived growth factor (PDGF), play crucial roles in bone metabolism[3,4]. The details behind the effects of incretin on bone metabolism have not yet been precisely elucidated

Methods

Results

Conclusion