title: The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone.
abstract: Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6(+/+) and IL-6(-/-) mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6(-/-) compared with IL-6(+/+) bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6(-/-) earlier than IL-6(+/+) marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6(-/-) marrow. In the skeletal system, although intermittent PTH administration to IL-6(+/+) and IL-6(-/-) mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-β1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system.
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109-1078, USA.
authors.forename: Sun Wook
authors.initials: SW
authors.lastname: Cho
authors.forename: Flavia Q
authors.initials: FQ
authors.lastname: Pirih
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Koh
authors.forename: Megan
authors.initials: M
authors.lastname: Michalski
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Eber
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ritchie
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sinder
authors.forename: Seojin
authors.initials: S
authors.lastname: Oh
authors.forename: Saja A
authors.initials: SA
authors.lastname: Al-Dujaili
authors.forename: JoonHo
authors.initials: J
authors.lastname: Lee
authors.forename: Ken
authors.initials: K
authors.lastname: Kozloff
authors.forename: Theodora
authors.initials: T
authors.lastname: Danciu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wronski
authors.forename: Laurie K
authors.initials: LK
authors.lastname: McCauley
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D010281:Parathyroid Hormone; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D053773:Transforming Growth Factor beta1; D050822:Cytokine Receptor gp130