title: Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts.
abstract: Inflammation has important roles in tissue regeneration, autoimmunity, and cancer. Different inflammatory stimuli can lead to bone loss by mechanisms that are not well understood. We show that skin inflammation induces bone loss in mice and humans. In psoriasis, one of the prototypic IL-17A-mediated inflammatory human skin diseases, low bone formation and bone loss correlated with increased serum IL-17A levels. Similarly, in two mouse models with chronic IL-17A-mediated skin inflammation,K14-IL17A(ind)andJunB(Δep), strong inhibition of bone formation was observed, different from classical inflammatory bone loss where osteoclast activation leads to bone degradation. We show that under inflammatory conditions, skin-resident cells such as keratinocytes, γδ T cells, and innate lymphoid cells were able to express IL-17A, which acted systemically to inhibit osteoblast and osteocyte function by a mechanism involving Wnt signaling. IL-17A led to decreased Wnt signaling in vitro, and importantly, pharmacological blockade of IL-17A rescued Wnt target gene expression and bone formation in vivo. These data provide a mechanism where IL-17A affects bone formation by regulating Wnt signaling in osteoblasts and osteocytes. This study suggests that using IL-17A blocking agents in psoriasis could be beneficial against bone loss in these patients.
authors.affiliation: Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Uluçkan
authors.affiliation: Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Jimenez
authors.affiliation: Center for Cardiology-Cardiology 1, University Medical Center, D-55131 Mainz, Germany. Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Karbach
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Jeschke
authors.affiliation: Bioinformatics Unit, Biotechnology Department, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Keller
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Busse
authors.affiliation: Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Croxford
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Finzel
authors.affiliation: Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Koenders
authors.affiliation: Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. ewagner@cnio.es.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology*; D019070:Cell Lineage; D002908:Chronic Disease; D004848:Epithelium / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology*; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D011565:Psoriasis; D012867:Skin / Q000473:pathology*; D060449:Wnt Signaling Pathway
chemical_list: D020381:Interleukin-17