The pathological role of Wnt5a in psoriasis and psoriatic arthritis

Abstract

Psoriasis (PsO) is a chronic inflammatory skin disease with both local and systemic components. PsO-associated arthritis, known as psoriatic arthritis (PsA), develops in approximately 13%-25% of PsO patients. Various factors associated with both PsO and PsA indicate that these conditions are part of a single disease. Identification of novel targets for the development of drugs to treat both PsO and PsA is desirable to provide more patient-friendly treatment regimens. Such targets will likely represent 'common checkpoints' of inflammation, for example key components or transduction cascades of the signalling pathways involved. Emerging evidence supports involvement of the non-canonical Wnt signalling pathways in the development of both PsO and PsA, especially the Wnt5a-activated signalling cascades. These, together with interlinked factors, are crucial in the interactions among keratinocytes, immune cells and inflammatory factors in PsO, as well as among chondrocytes, osteoblasts and osteoclasts that trigger both subchondral bone remodelling and cartilage catabolism in PsA. This review focuses on the pathological role of Wnt5a signalling and its interaction with other interlinked pathways in both PsO and PsA, and also on the main challenges for future research, particularly with respect to molecules targeting Wnt signalling pathways for the treatment of PsO and PsA.

Keywords: Wnt5a; immunity; keratinocyte; psoriasis; psoriatic arthritis; vascularity.

Figure 1

Model of the role and proposed mechanism of Wnt5a in psoriasis. Activation of Wnt5a signaling and its downstream effectors by local or systemic pathogens stimulate keratinocyte proliferation and secretion of inflammatory cytokines, which further regulate Wnt5a expression and promote keratinocyte proliferation and activation through Wnt5a‐mediated signalling pathways. This cross‐talk forms a signalling loop that promotes the persistence of PsO inflammation and disease progression

Figure 2

Model of the role and proposed mechanism of Wnt5a in psoriatic arthritis. Wnt5a produced by chondrocyte or osteoblast activated the non‐canonical signalling pathway and downstream cascades include CAMK Ⅱ, MAPKs, NF‐κB, JNK and/or PKC, Rho, thereby regulates the activity of chondrocytes, osteoblasts and osteoclasts, triggers both subchondral bone remodelling and cartilage catabolic metabolism, and finally lead to the development of psoriatic arthritis