title: Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone.
abstract: Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signalling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labelled surface and mineral apposition rate. By 26 weeks of age, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL-6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were also reduced in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity through the stimulation of osteoclast-derived "coupling factors" and "osteotransmitters", respectively.
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: Rachelle W
authors.initials: RW
authors.lastname: Johnson
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: Narelle E
authors.initials: NE
authors.lastname: McGregor
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Brennan
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: Blessing
authors.initials: B
authors.lastname: Crimeen-Irwin
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Poulton
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, VIC, Australia.
authors.forename: T John
authors.initials: TJ
authors.lastname: Martin
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, VIC, Australia. Electronic address: nsims@svi.edu.au.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism*; D002356:Cartilage / Q000378:metabolism; D056657:Cathepsin K / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000473:pathology; D017353:Gene Deletion; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis; D060888:Real-Time Polymerase Chain Reaction; D053702:Receptors, Interleukin-11 / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction; D055114:X-Ray Microtomography
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D053702:Receptors, Interleukin-11; D019947:Receptors, Interleukin-6; C577686:interleukin-6, mouse; D050822:Cytokine Receptor gp130; D056657:Cathepsin K
keywords: Bone formation; Cortical; Glycoprotein130; Osteoclast