title: Ras signaling regulates osteoprogenitor cell proliferation and bone formation.
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.
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Garyfallia
authors.initials: G
authors.lastname: Papaioannou
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Mirzamohammadi
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000071556:Cancellous Bone / Q000473:pathology; D002452:Cell Count; D019070:Cell Lineage; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D024043:Collagen Type II / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009857:Oncogenes; D009929:Organ Size; D010012:Osteogenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D024043:Collagen Type II; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); D000076182:Sp7 Transcription Factor; D014157:Transcription Factors; C479466:Sp7 protein, mouse; C495971:Hras protein, mouse