title: gp130 in late osteoblasts and osteocytes is required for PTH-induced osteoblast differentiation.
abstract: Parathyroid hormone (PTH) treatment stimulates osteoblast differentiation and bone formation, and is the only currently approved anabolic therapy for osteoporosis. In cells of the osteoblast lineage, PTH also stimulates the expression of members of the interleukin 6 (IL-6) cytokine superfamily. Although the similarity of gene targets regulated by these cytokines and PTH suggest cooperative action, the dependence of PTH anabolic action on IL-6 cytokine signaling is unknown. To determine whether cytokine signaling in the osteocyte through glycoprotein 130 (gp130), the common IL-6 superfamily receptor subunit, is required for PTH anabolic action, male mice with conditional gp130 deletion in osteocytes (Dmp1Cre.gp130(f/f)) and littermate controls (Dmp1Cre.gp130(w/w)) were treated with hPTH(1-34) (30 μg/kg 5× per week for 5 weeks). PTH dramatically increased bone formation in Dmp1Cre.gp130(w/w) mice, as indicated by elevated osteoblast number, osteoid surface, mineralizing surface, and increased serum N-terminal propeptide of type 1 collagen (P1NP). However, in mice with Dmp1Cre-directed deletion of gp130, PTH treatment changed none of these parameters. Impaired PTH anabolic action was associated with a 50% reduction in Pth1r mRNA levels in Dmp1Cre.gp130(f/f) femora compared with Dmp1Cre.gp130(w/w). Furthermore, lentiviral-Cre infection of gp130(f/f) primary osteoblasts also lowered Pth1r mRNA levels to 16% of that observed in infected C57/BL6 cells. In conclusion, osteocytic gp130 is required to maintain PTH1R expression in the osteoblast lineage, and for the stimulation of osteoblast differentiation that occurs in response to PTH.
authors.affiliation: St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Therese
authors.initials: T
authors.lastname: Standal
authors.affiliation: St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Rachelle W
authors.initials: RW
authors.lastname: Johnson
authors.affiliation: St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Narelle E
authors.initials: NE
authors.lastname: McGregor
authors.affiliation: St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Poulton
authors.affiliation: St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Patricia W M
authors.initials: PW
authors.lastname: Ho
authors.affiliation: St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: T John
authors.initials: TJ
authors.lastname: Martin
authors.affiliation: St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway St.Vincent's Institute of Medical Research9 Princes St, Fitzroy, Victoria 3065, AustraliaDepartment of Medicine at St. Vincent's Hospital MelbourneThe University of Melbourne, Fitzroy, Victoria, AustraliaDepartment of Cancer Research and Molecular MedicineThe KG Jebsen Center for Myeloma Research and Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway nsims@svi.edu.au.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics*; D010281:Parathyroid Hormone / Q000494:pharmacology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C494200:Il6st protein, mouse; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D050822:Cytokine Receptor gp130
keywords: PTH; PTH1R; bone formation; cortical; glycoprotein-130 (gp130); osteoblast; osteoclast; osteocyte; trabecular