Wnt7a Inhibits IL-1β Induced Catabolic Gene Expression and Prevents Articular Cartilage Damage in Experimental Osteoarthritis

Abstract

Wnt7a is a protein that plays a critical role in skeletal development. However, its effect on cartilage homeostasis under pathological conditions is not known. In this study, we found a unique inverse correlation between Wnt7a gene expression and that of MMP and IL-1β in individual human OA cartilage specimens. Upon ectopic expression in primary human articular chondrocytes, Wnt7a inhibited IL-1β-induced MMP and iNOS gene expression. Western blot analysis indicated that Wnt7a induced both canonical Wnt signaling and NFAT and Akt non-canonical signaling. Interestingly, inhibiting the canonical and Akt pathway did not affect Wnt7a activity. However, inhibiting the NFAT pathway impaired Wnt7a’s ability to inhibit MMP expression, suggesting that Wnt7a requires NFAT signaling to exert this function. In vivo, intraarticular injection of lentiviral Wnt7a strongly attenuated articular cartilage damage induced by destabilization of the medial meniscus (DMM) OA-inducing surgery in mice. Consistently, Wnt7a also inhibited the progressive increase of joint MMP activity in DMM animals. These results indicate that Wnt7a signaling inhibits inflammatory stimuli-induced catabolic gene expression in human articular chondrocytes and is sufficient to attenuate MMP activities and promote joint cartilage integrity in mouse experimental OA, demonstrating a novel effect of Wnt7a on regulating OA pathogenesis.

Bioluminescence and second harmonic generation imaging reveal dynamic changes in the inflammatory and collagen landscape in early osteoarthritis

“…The NFκB (Balb/C) reporter mouse NFκB-RE-luc, consisting of 6 NFκB response elements, was purchased from Taconic (NY, USA). Destabilization of the medial meniscus (DMM) surgery was performed on 8-week-old male mice according to established protocol [39][40][41]. Briefly, the right knee joint was opened along the medial border of the patellar ligament and the medial meniscotibial ligament was severed.…”

Roles of Wnt7a in embryo development, tissue homeostasis, and human diseases

“…However, Wnt7a was found to attenuate articular cartilage damage by inhibition of matrix metalloproteinase (MMP) and interleukin‐1β (IL‐1β) expression thereby maintaining joint cartilage integrity in mouse experimental osteoarthritis. Actually, an inverse correlation between Wnt7a expression and MMP and IL‐1β expression was observed in individual human osteoarthritis cartilage specimens …”

“…These observations demonstrate Wnt7a as a pro‐inflammatory factor. Paradoxically, ectopic expression of Wnt7a was shown to inhibit IL‐1β‐induced MMP and iNOS expression in mouse experimental osteoarthritis, indicating that Wnt7a functions as an anti‐inflammatory factor in this condition …”

“…Actually, an inverse correlation between Wnt7a expression and MMP and IL-1β expression was observed in individual human osteoarthritis cartilage specimens. 60…”

Pan-cancer analysis of the developmental pathways reveals non-canonical wnt signaling as a driver of mesenchymal-type tumors

“…WNT7A and FZD2 can participate in both canonical and non-canonical pathways. 15,17,25,26 For most of the other pathways, the EMT gene set clustered separately from the receptors and ligands. The expression of genes encoding FZD2 and several Wnt ligands, both those that are considered canonical (Wnt3, Wnt4, Wnt7b, Wnt10b) 16 and those that are non-canonical (Wnt5a, Wnt11), was significantly associated with poor survival in patients with renal cell carcinoma (RCC), which was a cancer with a high correlation between EMT enrichment and poor survival.…”