Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts
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Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. / Uluçkan, Özge; Jimenez, Maria; Karbach, Susanne; Jeschke, Anke; Graña, Osvaldo; Keller, Johannes; Busse, Björn; Croxford, Andrew L; Finzel, Stephanie; Koenders, Marije; van den Berg, Wim; Schinke, Thorsten; Amling, Michael; Waisman, Ari; Schett, Georg; Wagner, Erwin F.
in: SCI TRANSL MED, Jahrgang 8, Nr. 330, 16.03.2016, S. 330ra37.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts
AU - Uluçkan, Özge
AU - Jimenez, Maria
AU - Karbach, Susanne
AU - Jeschke, Anke
AU - Graña, Osvaldo
AU - Keller, Johannes
AU - Busse, Björn
AU - Croxford, Andrew L
AU - Finzel, Stephanie
AU - Koenders, Marije
AU - van den Berg, Wim
AU - Schinke, Thorsten
AU - Amling, Michael
AU - Waisman, Ari
AU - Schett, Georg
AU - Wagner, Erwin F
N1 - Copyright © 2016, American Association for the Advancement of Science.
PY - 2016/3/16
Y1 - 2016/3/16
N2 - 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.
AB - 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.
KW - Animals
KW - Bone Resorption
KW - Cell Lineage
KW - Chronic Disease
KW - Epithelium
KW - Female
KW - Gene Expression Regulation
KW - Humans
KW - Inflammation
KW - Interleukin-17
KW - Male
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Models, Biological
KW - Osteoblasts
KW - Osteocytes
KW - Osteogenesis
KW - Psoriasis
KW - Skin
KW - Wnt Signaling Pathway
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1126/scitranslmed.aad8996
DO - 10.1126/scitranslmed.aad8996
M3 - SCORING: Journal article
C2 - 27089206
VL - 8
SP - 330ra37
JO - SCI TRANSL MED
JF - SCI TRANSL MED
SN - 1946-6234
IS - 330
ER -