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.

Low back pain is one of the top disorders that leads to disability and affects disability-adjusted life years (DALY) globally. Intervertebral disc degeneration (IDD) and subsequent discogenic pain composed major causes of low back pain. Recent studies have identified several important risk factors contributing to IDD's development, such as inflammation, mechanical imbalance, and aging. Based on these etiology findings, three categories of animal models for inducing IDD are developed: the damage-induced model, the mechanical model, and the spontaneous model. These models are essential measures in studying the natural history of IDD and finding the possible therapeutic target against IDD. In this review, we will discuss the technical details of these models, the duration between model establishment, the occurrence of observable degeneration, and the potential in different study ranges. In promoting future research for IDD, each animal model should examine its concordance with natural IDD pathogenesis in humans. We hope this review can enhance the understanding and proper use of multiple animal models, which may attract more attention to this disease and contribute to translation research.

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