Irisin Ameliorates Intervertebral Disc Degeneration by Activating LATS/YAP/CTGF Signaling

Abstract

Unbalanced metabolism of an extracellular matrix (ECM) in nucleus pulposus cells (NPCs) is widely acknowledged as the primary cause of intervertebral disc degeneration (IDD). Irisin, a novel myokine, is cleaved from fibronectin type III domain-containing 5 (FNDC5) and has recently been proven to regulate the metabolism of ECM. However, little is known about its potential on NPCs and the development of IDD. Therefore, this study sought to examine the protective effects and molecular mechanism of irisin on IDD in vivo and in vitro. Decreased expression levels of FNDC5 and anabolism markers (COL2A1 and ACAN) but increased levels of catabolism markers (ADAMTS4) were found in degenerative nucleus pulposus (NP) tissues. In a punctured-induced rat IDD model, irisin treatment was found to significantly slow the development of IDD, and in TNF-α-stimulated NPCs, irisin treatment partly reversed the disorder of ECM metabolism. In mechanism, RNA-seq results suggested that irisin treatment affected the Hippo signaling pathway. Further studies revealed that with irisin treatment, the phosphorylation levels of key factors (LATS and YAP) were downregulated, while the expression level of CTGF was upregulated. Moreover, CTGF knockdown partially eliminated the protective effects of irisin on the metabolism of ECM in NPCs, including inhibiting the anabolism and promoting the catabolism. Taken together, this study demonstrated that the expression levels of FNDC5 were decreased in degenerative NP tissues, while irisin treatment promoted the anabolism, inhibited the catabolism of the ECM in NPCs, and delayed the progression of IDD via LATS/YAP/CTGF signaling. These results shed light on the protective actions of irisin on NPCs, leading to the development of a novel therapeutic target for treating IDD.

Continuous mechanical compression-induced intervertebral disc degeneration and pain in the caudal spine in rats

“…Interestingly, as the duration of caudal compression in rats increased or as the degree of human disc degeneration increased, YAP expression signi cantly decreased, while TAZ expression further increased, suggesting that these two components may play different roles. Most of the literature has reported that the expression of YAP can delay the progression of disc degeneration [29,[55][56][57][58], and the present study showed that YAP expression levels were signi cantly increased in mildly degenerated nucleus pulposus tissue but were decreased in severely degenerated nucleus pulposus tissue. Acute disc injury can cause the upregulation of YAP expression, suggesting that IVDD has a certain ability to repair itself [29].…”

Roles of organokines in intervertebral disc homeostasis and degeneration

“…A recent study suggested a correlation between LCN-2 and the expression of inflammation-related genes in human discs ( 114 ). Moreover, upregulated expression of LCN-2 has been validated to increase MMP-9 activity in AF cells ( 115 ). Considering that LCN-2 could function as a biomechanical and inflammatory sensor in bone–cartilage crosstalk, its specific role in IVDD needs to be elucidated ( 9 ).…”

“…Exercise elevated irisin levels in plasma and NP tissue and FNDC5/irisin knockout abolished the protective effects of exercise against IVDD in a murine model ( 114 ). By activating autophagy or large tumor suppressor kinase (LATS)/yes-associated protein (YAP)/connective tissue growth factor (CTGF, also known as CCN2) signaling, irisin can help maintain cellular activity and matrix metabolism balance and inhibit inflammatory effects, thereby decelerating the progression of IVDD ( 115 , 117 ).…”