## 6 The Role of miRNAs in IDD  
Exosomes may be promising diagnostic biomarkers due to their ability to incorporate several molecules including lipids, RNAs and proteins targeting specific recipient cells or tissues [124]. Interestingly, many studies have shown that several miRNAs can be predictive markers for IDDs. miRNAs are single-stranded and small non-coding RNAs that can bind to the 3\({}^{\prime}\)-untranslated region (3\({}^{\prime}\)-UTR) of target mRNA molecules, leading to their translational repression or degradation [125]. They represent key biomolecular players that regulate the expression of several target genes and are involved through various pathways in cell proliferation, apoptosis, immunomodulation, ECM anabolism and catabolism (Figure 4) [126]. The anti-apoptotic effects of exosomes from MSCs-derived CM were described in a study conducted by [PERSON] et al. These results seem to be partially mediated by the transfer of exosomal miR-21 associated with the downregulation of homologous phosphatase and tensin (PTEN), which leads to the activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway and the inhibition of TNF-\(\alpha\)-induced NPC apoptosis [127]. The regulatory role of miR-210 was also investigated. Indeed, miR-210 upregulation inhibited apoptosis in human NPCs, suggesting its involvement in the etiology of IDD [128]. It has hypothesized that increased miR-223 expression may be a predictive marker of chronic lumbar radicular pain, as it would be released from the NP following disc herniation [129]. Similarly, the transfection of miR-146a in bovine NPCs decreased IL-18-driven inflammatory and catabolic responses both in vitro and ex vivo [130]. [PERSON] et al. have reported that miR-494-5p was upregulated in NP tissues of a mouse IDD model, while tissue inhibitors of metalloproteinases-3 (TIMP-3) were downregulated. The reduced expression of this miRNA promoted viability and attenuated the apoptosis and senescence of NPCs [131]. The upregulation of miR-142-3p or miR-199 delivered by MSC-derived exosomes may protect NPC from injury through inhibition of mitogen-activated protein kinase (MAPK) signaling [132; 133]. In addition, miR-199a decreased MMP-2, MMP-6, TIMP-1 and apoptotic cells in a mouse model of IDD, while the expression of collagen type II, aggrecan, increased following the exposition to BMSC EVs in vitro [134]. Among other miRNAs previously identified, miR-27a was involved in the regulation of apoptotic pathways and in the prevention of IDD through the ability to suppress ECM degradation targeting MMP-13 [135; 136]. Similarly, under TNF-\(\alpha\) stimulation, exosomes extracted from BM-MSCs were able to secrete miR-532-5p. This exosomal miRNA has been linked to a reduction in apoptosis in NP cells and matrix degradation by targeting Ras association domain family 5 (RASSF5), attenuating disc degeneration [137]. [PERSON] et al. suggested the potential effect of MSC-derived exosomes on pyrotosis activation and the role of miR-410 as a specific mediator of NPC pyrotosis [138]. Activating transcription factor 6 (ATF6) is a transcription factor identified as the target gene of miR-31-5p. When miR-31-5p was upregulated, the expression of ATF6 and other proteins involved in oxidative stress-induced ER-stress was suppressed, resulting in a protective effect in IDD [139]. Figure 4: Potential therapeutic role of exosomes in IDD through the modulation of ER stress, stimulation of production of ECM components, anti-apoptotic and anti-inflammatory effects on NP cells. BM-MSCs = bone marrow-derived stem cells; ECM = extracellular matrix; ER = endoplasmic reticulum; NP = nucleus pulposus; NPC = nucleus pulposus cell. Created with BioRender.com (accessed on 10 October 2021). Another family of molecules delivered by exosomes is represented by circular noncoding RNAs (circRNAs). CircRNAs may act as post-transcriptional regulators and interact with miRNAs as miRNA sponges.