Wnt signaling: a promising target for osteoarthritis therapy

Abstract

Osteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. Characterized by degradation of articular cartilage, synovial inflammation, and changes in periarticular and subchondral bone, OA can negatively impact an individual's physical and mental well-being. Recent studies have reported several critical signaling pathways as key regulators and activators of cellular and molecular processes during OA development. Wnt signaling is one such pathway whose signaling molecules and regulators were shown to be abnormally activated or suppressed. As such, agonists and antagonists of those molecules are potential candidates for OA treatment. Notably, a recent phase I clinical trial (NCT02095548) demonstrated the potential of SM04690, a small-molecule inhibitor of the Wnt signaling pathway, as a disease-modifying oseoarthritis drug (DMOAD). This review summarizes the role and mechanism of Wnt signaling and related molecules in regulating OA progression, with a view to accelerating the translation of such evidence into the development of strategies for OA treatment, particularly with respect to potential applications of molecules targeting the Wnt signaling pathway.

Keywords: Chondrocyte; Osteoarthritis; Osteoblast; Osteoclast; Synoviocyte; Wnt signaling pathway.

Fig. 1

The signaling transduction cascades and cell-specific role of β-catenin-dependent canonical Wnt signaling pathway in regulating chondrocyte, synovial cells and osteoblast metabolism, whereby mediating the process of cartilage degradation, synovium inflammation, as well abnormally activited subchondral bone remodelling in OA development. Events induced by Wnt or β-catenin targeted angonist of antagonist/inhibitor, including DKK1, WISP-1, FRZB, SOST and Fibutlin-4, are marked with event-specific colored line or arrows

Fig. 2

The signaling transduction cascades and cell-specific role of noncanonical Wnt signaling, predominantly activated by wnt5a, in regulating chondrocyte, synovial cells, osteoblast and osteoclast metabolism, including mediated IL-1 beta stimulated chondrocyte catabolism, TNF-alpha and IL-17A induced synovium inflammation, as well abnormal mineralization of osteoblast and osteoclast differentiation, all these process are promised to be involved in OA development

Fig. 3

Proposed model of the role of canonical and noncanonical wnt signaling pathway mediated network that regulating chondrocyte function, the activiation of Wnt signaling and their interaction between either canonical and noncanonical, or Hedgehog, MAPK, NF/κB, BMP/TGF-β/Smad and Notch signaling pathways, are assiciated with chondrocyte differentiation, hypertrophy, catabolism, anabolism and thereby involed in OA development, and marked with event-specific colored line or arrows

Fig. 4

WISP stimulates MMPs expression in synovium and cartilage through inhibiting TGF-b /Smad 2/3 signaling and activating the accumulation of b-catenin, which serves to enhance the synovium inflammation

Fig. 5

Interaction within TGF-b/BMP, canonical and non-canonical signaling pathway in osteoblast, in addition to induces DKK2 to inhibit the canonical Wnt signaling pathway, TGF-b/BMP signaling also up-regulates the expression of Wnt5a In osteoblasts, and subsequently stimulating the expression of a number of genes involved with osteogenesis