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.
Highlights
The Wnt pathway is a highly conserved signaling pathway that plays a crucial role in development and disease[7,8]
We found that higher expression of Wnt7a trended with lower expression of MMP1, MMP13, and IL-1β.Vice versa, lower expression of Wnt7a paired with higher expression of MMP1, MMP13, and IL-1β
When Wnt7a expression surpassed a certain level, it was correlated with a dramatic decrease in the catabolic gene expression, and these samples tended to be the normal cartilage specimens with little cartilage damage
Summary
The Wnt pathway is a highly conserved signaling pathway that plays a crucial role in development and disease[7,8]. Inconclusive results have been seen related to calcium signaling[24,25,26,27] Perhaps such seemingly contradictory data indicate that an intricate balance in Wnt signaling must be maintained for optimal cartilage homeostasis. Additional studies indicated that Wnt3a decreased MMP expression under IL-1βtreatment and normal conditions in human chondrocytes[33]. While it has been shown to be expressed in articular cartilage[10], the effect of Wnt7a in OA or human chondrocytes under pathological conditions has not been examined. We further examined the effect of Wnt7a ectopic expression in human primary articular chondrocytes under inflammatory conditions, as well as in the destabilization of the medial meniscus (DMM) surgery OA mouse model. Our results indicate a beneficial effect of Wnt7a on chondrocytes in vitro and in vivo, and suggest that NFAT signaling is necessary for this effect of Wnt7a
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