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Sci Transl Med. 2016 Mar 16;8(330):330ra37. doi: 10.1126/scitranslmed.aad8996. Epub 2016 Mar 16.

Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts.

Author information

1
Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
2
Center for Cardiology-Cardiology 1, University Medical Center, D-55131 Mainz, Germany. Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany.
3
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
4
Bioinformatics Unit, Biotechnology Department, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
5
Institute of Molecular Medicine, University of Mainz, D-55131 Mainz, Germany.
6
Department of Internal Medicine 3, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
7
Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, Netherlands.
8
Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. ewagner@cnio.es.

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.

PMID:
27089206
DOI:
10.1126/scitranslmed.aad8996
[Indexed for MEDLINE]

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