title: Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling.
abstract: Cardiotrophin (CT-1) signals through gp130 and the LIF receptor (LIFR) and plays a major role in cardiac, neurological, and liver biology. We report here that CT-1 is also expressed within bone in osteoclasts and that CT-1 is capable of increasing osteoblast activity and mineralization both in vitro and in vivo. Furthermore, CT-1 stimulated CAAT/enhancer-binding protein-delta (C/EBP delta) expression and runt-related transcription factor 2 (runx2) activation. In neonate CT-1(-/-) mice, we detected low bone mass associated with reduced osteoblasts and many large osteoclasts, but increased cartilage remnants within the bone, suggesting impaired resorption. Cultured bone marrow (BM) from CT-1(-/-) mice generated many oversized osteoclasts and mineralized poorly compared with wildtype BM. As the CT-1(-/-) mice aged, the reduced osteoblast surface (ObS/BS) was no longer detected, but impaired bone resorption continued resulting in an osteopetrotic phenotype in adult bone. CT-1 may now be classed as an essential osteoclast-derived stimulus of both bone formation and resorption.
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Walker
authors.forename: Narelle E
authors.initials: NE
authors.lastname: McGregor
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Poulton
authors.forename: Sueli
authors.initials: S
authors.lastname: Pompolo
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Allan
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Quinn
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Gillespie
authors.forename: T John
authors.initials: TJ
authors.lastname: Martin
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D016723:Bone Remodeling; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D016207:Cytokines / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta; C092073:cardiotrophin 1