Table 2.

Key findings of the included studies.

Author	Key Findings
Song et al. 2022 [32]	The RhoA/MRTF-A signaling pathway is activated by mechanical stress and promotes ECM degeneration in the NP. The RhoA/MRTF-A axis regulates MMP-12 and CTGF expression. NP degeneration caused by mechanical stress overload is mitigated by the RhoA/MRTF-A inhibitor CCG-1423, which has the potential therapeutic effect of NPCs’ functional recovery facilitation.
Sun et al. 2020 [33]	HUVECs’ migration is strongly inhibited by 0.5 Mpa/NC-exos, showing a dose-dependent effect. Thus, NC-exos induced by compressive load have the potential to inhibit endothelial cell angiogenesis. The anti-angiogenic role of 0.5 Mpa/NC-exos appears to be mediated by miRNAs transferred from NCs to endothelial cells via NC-exos. Among these miRNAs, the upregulation of miR-140-5p shows a significant inhibitive effect on angiogenesis in endothelial cells via the downregulation of Wnt11 expression and inhibition of b-catenin nuclear accumulation.
Cambria et al. 2020 [34]	A TRPV4 antagonist has shown the capacity to lessen the mechanoflammation caused by hyperphysiological CTS, thus revealing the novel mechanoinflammatory role of TRPV4 in human primary AF cells. TRPV4 mediates stretch-induced inflammation, possibly via the activation of the p38 MAPK pathway. TRPV4 KO via CRISPR-Cas9 prevents the stretch-induced upregulation of IL8 mRNA and tends to reduce the stretch-induced IL6 mRNA.
Franco-Obregon et al. 2018 [35]	IVD cells exposed to simulated microgravity or to TRPC channel inhibition showed reduced proliferation and increased senescence. The TRPC6 gene expression was reduced in cells subjected to simulated microgravity. Mechanotransduction, cell proliferation and senescence regulation in IVDs may be partially controlled by TRPC6 ion channels.
Hodson et al. 2018 [36]	NP cells cultured both at pH 7.1 and 6.5 showed similar gene expression patterns. NP cells’ response to compression shifted from matrix homeostasis at a pH of 7.1, representative of non-degenerated tissue, to matrix catabolism at a pH of 6.5, representative of degenerated tissue. Thus, a catabolic shift in human NP cell phenotype occurred under acidic pH conditions. The aberrant mechanotransduction induced by an acidic environment may have a potential role in the progression of IVD degeneration.
Likhitpanichkul et al. 2016 [37]	TNF-α-treated AF cells showed increased IL-1β and IL-8 production and cytoskeletal network modification with enhanced stress fiber formation from actin polymerization and microtubule network disruption; these cytoskeletal changes reflect increased mechanosensitivity. Pro-inflammatory cytokines produced by IVD cells may be a key factor in the inflamed environment associated with IVD degeneration, potentially altering physiological IVD mechanobiology.
Gilbert et al. 2013 [38]	RGD-recognizing integrins may not be involved in the altered mechanoresponse of AF cells derived from degenerate IVDs. The aberrant response in degenerate cells may be recognized by different mechanoreceptors via an alternative mechanotransduction pathway. The involvement of RGD integrins in mechanoresponses appeared to be lost with degeneration. The findings suggested FAK activation is caused by CTS via an RGD-integrin-dependent pathway. The ADAMTS-4 decreased gene expression seen in CTS-stimulated non-degenerated AF cells may occur through an integrin-, and potentially FAK-, dependent mechanism. Non-degenerated AF cells’ mechanoresponse to CTS appears to be mediated by RGD-recognizing integrins. The aforementioned cells showed the integrin-dependent phosphorylation of FAK in response to strain stimulation. RGD integrins and FAK may not be involved in the mechanoresponse of degenerated AF cells.
Gilbert et al. 2011 [39]	For the first time, immunopositivity for the IL-4r subunits IL-4Ra and IL2Rg and immunonegativity for the receptor subunit IL-13Ra1 was described in human IVD cells. Stimulated with CTS, AF cells derived from non-degenerative IVDs showed a shift to a less catabolic phenotype. The reduced catabolic response appeared to be IL-1- and IL-4-dependent. The increment in MMP-3 gene expression may be correlated with its decreased activity (negative feedback regulation). The inhibition of MMPs’ activity due to IL-1Ra treatment seems to have determined increased MMP gene expression in IVD cells, outlining the potential of targeting IL-1R in DDD treatment. The findings show the potential role of IL-1, not only in a catabolic shift typical of DDD, but also in transducing physiological mechanical stimuli, leading to tissue remodeling. Neither IL-1 nor IL-4 appeared to be necessary for the matrix remodeling mechanoresponse of AF cells derived from degenerative IVDs. AF cells derived from degenerative and non-degenerative tissue regulated matrix protein and matrix-degrading enzyme gene expression differently; this difference may be determined by altered cytokine-dependent transcription factor activation.
Huang et al. 2011 [40]	Compressive load, with the increase in ADAMTS-1, 4, 5 expression, appears to be a key factor in aggrecan depletion in human NP cells, which might have an etiologic implication in the development of IDD. The physiological expression of ADAMTS-1, 4, 9, 15 and TIMP-3 in non-degenerative discs indicates a possible role for these proteins in the normal turn-over of aggrecan and other matrix molecules in the healthy disc matrix. The imbalance between ADAMTSs and their inhibitor (TIMP-3) could play a role in the pathogenesis of IDD. TIMP-3 might be a potent therapeutic target preventing aggrecan loss during IDD.
Gilbert et al. 2010 [41]	The response of AF cells derived from both degenerative and non-degenerative IVDs to CTS appeared to be frequency-dependent. At 1 Hz of CTS (similar to normal physiologic motion), AF cells derived from non-degenerative tissue showed a shift to a less catabolic phenotype. The 0.33 Hz of CTS resulted in a catabolic response. The response of AF cells to CTS was both frequency-dependent and dependent on whether the cells are derived from degenerated or non -degenerated tissue. AF cells derived from degenerated tissue not only lost their ability to downregulate matrix enzyme gene expression in response to a 1.0 Hz frequency of CTS but also responded by reducing their matrix protein gene expression. Matrix homeostasis and matrix anabolism are promoted by physiological mechanical loads in healthy disc cells. Frequencies below physiological levels could lead to the degradation of the IVD matrix. On the contrary, physiologic mechanical loads could be detrimental to disc cell matrix homeostasis in degenerated IVDs, potentially leading to the progression of DDD.
Neidlinger-Wilke et al. 2009 [42]	Relative expression levels of PTN in human IVD cells are influenced by mechanical load. Increased PTN expression may have pro-angiogenic effects, which could be either enforced or impaired by the down- or upregulation of the antiangiogenic protein aggrecan. PTN expression showed high variability between different patients; this variation may be attributable to different degrees of disc degeneration. Mechanical load influences the presence of angiostatic and angiogenic factors within the IVD.
Le Maitre et al. 2009 [43]	In non-degenerated IVDs, RGD-binding integrins contribute to the mechanotransduction response. Mechanotransduction pathways appeared to be altered in NP cells derived from degenerative IVDs. Mechanosensing in NP cells from non-degenerative discs occurred via RGD integrins, possibly via the a5b1-integrin, while cells from degenerated discs might use a different receptor to sense and respond to mechanical signaling. Since the a5b1 integrin is physiologically expressed in degenerated IVDs, with no change in expression observed during disc degeneration, the cited mechanosensing could occur through a non-RGD integrin.
Le Maitre et al. 2008 [44]	IVD cells modify matrix homeostasis in response to physiological hydrostatic pressure. Cells obtained from healthy IVD tissues respond to dynamic HP by upregulating the gene expression of anabolic genes, indicative of healthy matrix homeostasis. Altered mechanotransduction pathways may be operational in degenerative IVD tissues.
Aladin et al. 2007 [45]	A non-degenerated (COL9 A2 Trp2+) control group appeared to have an increasing swelling stress pattern. Degenerated (COL9 A2Trp2-) groups exhibited decreasing swelling stress patterns. The non-degenerated (Trp2+) and degenerated (Trp2-) groups’ swelling pressure and compressive modulus were considerably lower than those of the non-degenerated (Trp2-) controls. A significant difference occurred in the swelling pressure (p = 0.006) and compressive modulus (p = 0.025) between the non-degenerated (Trp2-) controls and (Trp2+) cases. The swelling pressure difference between degenerated (Trp2+) controls and (Trp2-) cases was not significant (p = 0.34), suggesting that the Trp2 allele is related with a decrease in the swelling pressure to an extent approximately similar to but slightly better than that of the degenerated discs. The Trp2 allele seems to be linked to IVD mechanical properties and consequently to disc degeneration pathomechanism. Alterations in collagen IX result in cross-linking abnormalities between collagen IX and collagen II, thus reducing the ability of the collagen network to hold the ECM together, manifested as changes in the compression modulus and swelling pressure. The Trp2 allele is associated with deteriorating mechanical properties of the nucleus pulposus as early as adolescence, with no other signs of disc degeneration.
Neidlinger-Wilke et al. 2005 [46]	CTS appeared to have an anabolic effect both in AF and NP cells, apparently without differences among different strain magnitudes. The application of mechanical stimuli had no negative effect on IVD cells. Hydrostatic pressure also appeared to determine an anabolic effect in both AP and NP cells. Anulus cells were more responsive to cyclic strain, whereas nucleus cells were more responsive to hydrostatic pressure. Mechanically stimulated disc cells, either subjected to hydrostatic pressure or cyclic strain, tended to decrease the mRNA expression of MMP-2 and -3. These findings seem to suggest that moderate mechanical loading may prevent disc matrix degradation via the suppression of cellular production of MMPs. Cells obtained from different donor patients showed high inter-individual variations, which could be influenced by the degree of degeneration of the disc samples.