Ras signaling regulates osteoprogenitor cell proliferation and bone formation.

Garyfallia Papaioannou,Tatsuya Kobayashi,Fatemeh Mirzamohammadi

doi:10.1038/cddis.2016.314

Garyfallia Papaioannou, Tatsuya Kobayashi + Show 1 more

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https://doi.org/10.1038/cddis.2016.314

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Abstract

During endochondral bone development, osteoblasts are continuously differentiated from locally residing progenitor cells. However, the regulation of such endogenous osteoprogenitor cells is still poorly understood mainly due to the difficulty in identifying such cells in vivo. In this paper, we genetically labeled different cell populations of the osteoblast linage using stage-specific, tamoxifen-inducible Cre transgenic mice to investigate their responses to a proliferative stimulus. We have found that overactivation of Kras signaling in type II collagen-positive, immature osteoprogenitor cells, but not in mature osteoblasts, substantially increases the number of their descendant stromal cells and mature osteoblasts, and subsequently increases bone mass. This effect was mediated by both, the extracellular signal-regulated kinase (ERK) and phosphoinositide 3 kinase (PI3K), pathways. Thus we demonstrate that Ras signaling stimulates proliferation of immature osteoprogenitor cells to increase the number of their osteoblastic descendants in a cell-autonomous fashion.

Highlights

Bones are formed and maintained by multiple types of bone cells.[1]
We have found that overactivation of Kras signaling in type II collagen-positive, immature osteoprogenitor cells, but not in mature osteoblasts, substantially increases the number of their descendant stromal cells and mature osteoblasts, and subsequently increases bone mass
We investigated the role of Ras signaling in three different cell populations of the osteoblast lineage, that is, Col2, Osx- and Col1-positive cells, during bone development

Summary

Introduction

Bones are formed and maintained by multiple types of bone cells.[1]. Mineralized bone matrix is produced by osteoblasts. Osteoblasts produce a large amount of bone matrix proteins including type I collagen and osteocalcin. Osteoblasts die or further differentiate into osteocytes that are embedded in the bone matrix.[2,3] Bone is constantly remodeled throughout life. During this process, osteoblasts are continuously differentiated from locally residing mesenchymal progenitor cells. Proliferation and differentiation of the osteoblast progenitors need to be well coordinated to maintain adequate bone mass and function. In this study, using stage-specific, tamoxifen-inducible Cre transgenic lines, we demonstrate that Ras signaling regulates proliferation of Col2-positive osteoprogenitor cells and controls bone mass, whereas Ras overactivation shows little effect in mature osteoblasts. The difference of responsiveness to Ras signaling discriminates differentiation stages of cells of the osteoblast lineage

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