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.

Augmented Th17 Differentiation Leads to Cutaneous and Synovio‐Entheseal Inflammation in a Novel Model of Psoriatic Arthritis

“…This suggested an indirect pathway where IL-17 from Th17 cells acted on mesenchymal cells including osteoblasts and fibroblasts which then upregulated the expression of RANKL to drive osteoclast differentiation. Besides promoting osteoclastogenesis, defects in osteoblast differentiation using bone marrow from R26STAT3C stopfl/fl CD4Cre mice suggested a suppressive role of Th17 cytokines on these bone-forming cells consistent with the recent observations of Wagner and colleagues, who recently demonstrated in two murine psoriasis models that IL-17 suppressed osteoblast and osteocyte differentiation[45]. …”

Simultaneous quantification of bone erosions and enthesiophytes in the joints of patients with psoriasis or psoriatic arthritis - effects of age and disease duration

“…The influence of inflammation as an enhancer of progression of bone erosions is also supported by the notion that the duration of PsA is associated with the burden of bone erosions. This clinical observation is substantiated by earlier mechanistic data showing that key cytokines involved in the pathogenesis of psoriatic disease, like IL-17 and TNF-alpha, potently affect bone homeostasis by enhancing bone resorption while suppressing bone formation [21–24]. Hence the longer the bone is exposed to the inflammatory micro-environment in PsA, the more likely bone erosion occurs.…”

Integration of T‐cell receptor, Notch and cytokine signals programs mouse γδ T‐cell effector differentiation

“…Depending on the context, the same effector functions that make γδ T cells an important arm of the immune system can alternatively contribute to the development, progression and exacerbation of various diseases. These harmful effects include roles in the pathogenesis of autoimmune conditions such as psoriasis, multiple sclerosis, and arthritis, as well as contributions to breast cancer metastasis and bone loss 3–7 . Given that the beneficial and deleterious effects of γδ T cells are largely attributable to the ability of these cells to rapidly produce high levels of inflammatory cytokines, it is important to understand the development and function of the major effector subtypes.…”