title: Erythropoietin mediated bone formation is regulated by mTOR signaling.
abstract: The role of erythropoietin (Epo) and Epo/Epo receptor (EpoR) signaling pathways for production of red blood cells are well established. However, little is known about Epo/EpoR signaling in non-hematopoietic cells. Recently, we demonstrated that Epo activates JAK/STAT signaling in hematopoietic stem cells (HSCs), leading to the production of bone morphogenetic protein 2 (BMP2) and bone formation and that Epo also directly activates mesenchymal cells to form osteoblasts in vitro. In this study, we investigated the effects of mTOR signaling on Epo-mediated osteoblastogenesis and osteoclastogenesis. We found that mTOR inhibition by rapamycin blocks Epo-dependent and -independent osteoblastic phenotypes in human bone marrow stromal cells (hBMSCs) and ST2 cells, respectively. Furthermore, we found that rapamycin inhibits Epo-dependent and -independent osteoclastogenesis in mouse bone marrow mononuclear cells and Raw264.7 cells. Finally, we demonstrated that Epo increases NFATc1 expression and decreases cathepsin K expression in an mTOR-independent manner, resulting in an increase of osteoclast numbers and a decrease in resorption activity. Taken together, these results strongly indicate that mTOR signaling plays an important role in Epo-mediated bone homeostasis.
authors: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109-1078, USA.
authors: Jinkoo
authors: J
authors: Kim
authors: Younghun
authors: Y
authors: Jung
authors: Hongli
authors: H
authors: Sun
authors: Jeena
authors: J
authors: Joseph
authors: Anjali
authors: A
authors: Mishra
authors: Yusuke
authors: Y
authors: Shiozawa
authors: Jingcheng
authors: J
authors: Wang
authors: Paul H
authors: PH
authors: Krebsbach
authors: Russell S
authors: RS
authors: Taichman
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism*; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D017154:Stromal Cells / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D056657:Cathepsin K; D020123:Sirolimus