Ras signaling regulates osteoprogenitor cell proliferation and bone formation

• Published in: Cell death & disease Vol. 7; no. 10; p. e2405
• Main Authors: Papaioannou, Garyfallia, Mirzamohammadi, Fatemeh, Kobayashi, Tatsuya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.10.2016; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/136/142; 631/136/818; 631/80/86; 692/698/690/796; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Bones; Cancellous Bone - pathology; Cell Biology; Cell Count; Cell Culture; Cell growth; Cell Lineage; Cell Proliferation; Cell Self Renewal; Collagen Type II - metabolism; Immunology; Life Sciences; MAP Kinase Signaling System; Mice; Oncogenes; Organ Size; Original; original-article; Osteogenesis; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins p21(ras) - metabolism; Signal Transduction; Sp7 Transcription Factor; Stem Cells - cytology; Stem Cells - metabolism; Stromal Cells - metabolism; Stromal Cells - pathology; Transcription Factors - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.314

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.