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), P1NP levels as well as bone formation rates were decreased in mice with an epithelial (Keratin5)-specific deletion of JunB (JunBΔep). Moreover, transgenic mice expressing IL-17A in keratinocytes exhibit decreased OCN and P1NP levels with no changes in TRAcP5 levels. Expression of Phex, Dmp1 and Sost, markers of osteocytes, were altered in both models of skin inflammation. The inhibition of bone formation by IL-17A was independent of its expression in T-cells, since JunBΔep mice on a Rag-/- background displayed decreased levels of OCN. Importantly, pharmacologic IL-17A blockade rescued Ocn expression and bone formation rates in JunBΔep mice. Mechanistically, IL-17A inhibits osteoblast maturation and mineralization in vitro. RNA-seq analyses from in vitro osteoblast cultures treated with IL-17A identified nitric oxide and lipocalin-2 (Lcn-2) as mediators of IL-17A-dependent osteoblast inhibition. In vivo, crossing JunBΔep mice to Lcn-2-deficient mice reduced bone loss. Importantly, psoriasis patients without arthritis developed 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.
Disclosure: The authors declared no competing interests. ÖU: EMBO Long-term fellowship (LT-1244-2009), ECTS-AMGEN bone biology fellowship. AW by SFB: TRR 128 TPA7; EFW by the BBVA Foundation and a European Research Council Advanced Grant (ERC FCK/2008/37); GS and AW by DFG (Project SPP1468 Immunobone), the Marie Curie Osteoimmune and the IMI funded project BTCure.