ECTS2014 Hot Topic Oral Communications (1) (5 abstracts)
Skin inflammation causes bone loss with reduced bone formation through systemic IL-17A release
Ozge Uluckan 1 , Johannes Keller 2 , Susanne Karbach 3 , Andrew Croxford 3 , Stephanie Finzel 4 , Marije Koenders 5 , Wim Van Den Berg 5 , Michael Amling 2 , Ari Waisman 3 , Georg Schett 4 & Erwin Wagner 1
1Spanish National Cancer Center, Madrid, Spain; 2University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3University of Mainz, Mainz, Germany; 4University of Erlangen-Nuremberg, Erlangen, Germany; 5Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Patients with chronic inflammatory diseases such as psoriasis are at high risk for developing osteoporosis. Psoriatic arthritis patients exhibit bone loss caused by increased bone resorption through activation of osteoclasts. However, it is not clear whether psoriasis can lead to bone loss in the absence of arthritis. Using mouse models with skin inflammation as well as psoriasis patient samples, we show that increased circulating IL-17A from the inflamed skin triggers bone loss through inhibition of bone formation. Osteocalcin (OCN) levels as well as bone formation rates are decreased in mice with an epithelial(Keratin5)-specific deletion of JunB (JunBΔep). Furthermore, transgenic mice expressing IL-17A in keratinocytes and mice injected with Adenoviruses expressing IL-17A exhibit decreased OCN levels. We show for the first time that, together with the previously-described γδT-cells, keratinocytes of epithelial origin also express IL-17A, which is transcriptionally controlled by JunB/AP-1. The inhibition of bone formation by IL-17A is independent of its expression by T/B-cells, since JunBΔep mice on a Rag1-/- background still display decreased levels of OCN. Mechanistically, through RNAseq analyses in osteoblasts, we identified nitric oxide and lipocalin-2 as mediators of IL-17A-dependent osteoblast inhibition. Pharmacologic IL-17A blockade rescues OCN expression and bone formation rates in JunBΔep mice. Importantly, psoriasis patients without arthritis develop bone loss with decreased OCN levels and increased serum IL-17A levels. Therefore, this study suggests that IL-17A, upregulated in inflammatory and autoimmune diseases, provides a risk for bone loss and its blockade should be considered in such diseases to prevent the adverse consequences on the skeleton.
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Bone Abstracts
ISSN 2052-1219 (online)
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