title: C-Mpl Is Expressed on Osteoblasts and Osteoclasts and Is Important in Regulating Skeletal Homeostasis.
abstract: C-Mpl is the receptor for thrombopoietin (TPO), the main megakaryocyte (MK) growth factor, and c-Mpl is believed to be expressed on cells of the hematopoietic lineage. As MKs have been shown to enhance bone formation, it may be expected that mice in which c-Mpl was globally knocked out (c-Mpl(-/-) mice) would have decreased bone mass because they have fewer MKs. Instead, c-Mpl(-/-) mice have a higher bone mass than WT controls. Using c-Mpl(-/-) mice we investigated the basis for this discrepancy and discovered that c-Mpl is expressed on both osteoblasts (OBs) and osteoclasts (OCs), an unexpected finding that prompted us to examine further how c-Mpl regulates bone. Static and dynamic bone histomorphometry parameters suggest that c-Mpl deficiency results in a net gain in bone volume with increases in OBs and OCs. In vitro, a higher percentage of c-Mpl(-/-) OBs were in active phases of the cell cycle, leading to an increased number of OBs. No difference in OB differentiation was observed in vitro as examined by real-time PCR and functional assays. In co-culture systems, which allow for the interaction between OBs and OC progenitors, c-Mpl(-/-) OBs enhanced osteoclastogenesis. Two of the major signaling pathways by which OBs regulate osteoclastogenesis, MCSF/OPG/RANKL and EphrinB2-EphB2/B4, were unaffected in c-Mpl(-/-) OBs. These data provide new findings for the role of MKs and c-Mpl expression in bone and may provide insight into the homeostatic regulation of bone mass as well as bone loss diseases such as osteoporosis.
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: Tomas E
authors.initials: TE
authors.lastname: Meijome
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: Jenna T B
authors.initials: JTB
authors.lastname: Ekwealor
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: R Adam
authors.initials: RA
authors.lastname: Hooker
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.|Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Ciovacco
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: Sanjeev M
authors.initials: SM
authors.lastname: Balamohan
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: Trishya L
authors.initials: TL
authors.lastname: Srinivasan
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: Brahmananda R
authors.initials: BR
authors.lastname: Chitteti
authors.affiliation: Department of Oral Biology, Indiana University School of Dentistry, Indiana, Indianapolis.
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Eleniste
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Horowitz
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indiana, Indianapolis.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.affiliation: Department of Oral Biology, Indiana University School of Dentistry, Indiana, Indianapolis.
authors.forename: Angela
authors.initials: A
authors.lastname: Bruzzaniti
authors.affiliation: Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences, Indiana, Indianapolis.
authors.forename: Robyn K
authors.initials: RK
authors.lastname: Fuchs
authors.affiliation: Department of Orthopaedic Surgery, Indiana University School of Medicine, Indiana, Indianapolis.|Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Kacena
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D012886:Skull / Q000166:cytology / Q000378:metabolism; D013926:Thrombopoietin / Q000235:genetics* / Q000378:metabolism
chemical_list: C000601240:EFNB2 protein, mouse; D036388:Ephrin-B2; C481270:Mpl protein, mouse; D053244:Osteoprotegerin; D053245:RANK Ligand; D053628:Receptors, Thrombopoietin; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D013926:Thrombopoietin; C586311:Ephb2 protein, mouse; C086681:Ephb4 protein, mouse; D036183:Receptor, EphB2; D036224:Receptor, EphB4
keywords: BONE MASS; C-Mpl; OSTEOBLASTS; OSTEOCLASTS; THROMBOPOIETIN