title: A novel role for thrombopoietin in regulating osteoclast development in humans and mice.
abstract: Emerging data suggest that megakaryocytes (MKs) play a significant role in skeletal homeostasis. Indeed, osteosclerosis observed in several MK-related disorders may be a result of increased numbers of MKs. In support of this idea, we have previously demonstrated that MKs increase osteoblast (OB) proliferation by a direct cell-cell contact mechanism and that MKs also inhibit osteoclast (OC) formation. As MKs and OCs are derived from the same hematopoietic precursor, in these osteoclastogenesis studies we examined the role of the main MK growth factor, thrombopoietin (TPO) on OC formation and bone resorption. Here we show that TPO directly increases OC formation and differentiation in vitro. Specifically, we demonstrate the TPO receptor (c-mpl or CD110) is expressed on cells of the OC lineage, c-mpl is required for TPO to enhance OC formation in vitro, and TPO activates the mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappaB signaling pathways, but does not activate the PI3K/AKT pathway. Further, we found TPO enhances OC resorption in CD14+CD110+ human OC progenitors derived from peripheral blood mononuclear cells, and further separating OC progenitors based on CD110 expression enriches for mature OC development. The regulation of OCs by TPO highlights a novel therapeutic target for bone loss diseases and may be important to consider in the numerous hematologic disorders associated with alterations in TPO/c-mpl signaling as well as in patients suffering from bone disorders.
authors: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Monique
authors: M
authors: Bethel
authors: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.
authors: Calvin L T
authors: CL
authors: Barnes
authors: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Amanda F
authors: AF
authors: Taylor
authors: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Ying-Hua
authors: YH
authors: Cheng
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Brahmananda R
authors: BR
authors: Chitteti
authors: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.
authors: Mark C
authors: MC
authors: Horowitz
authors: Department of Oral Biology, Indiana University School of Dentistry, Indianapolis, Indiana.|Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Angela
authors: A
authors: Bruzzaniti
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Edward F
authors: EF
authors: Srour
authors: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.|Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.|Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Melissa A
authors: MA
authors: Kacena
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053628:Receptors, Thrombopoietin / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects; D013926:Thrombopoietin / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins; D013926:Thrombopoietin
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