In Situ Cell Signalling of the Hippo-YAP/TAZ Pathway in Reaction to Complex Dynamic Loading in an Intervertebral Disc Organ Culture

Abstract

Recently, a dysregulation of the Hippo-YAP/TAZ pathway has been correlated with intervertebral disc (IVD) degeneration (IDD), as it plays a key role in cell survival, tissue regeneration, and mechanical stress. We aimed to investigate the influence of different mechanical loading regimes, i.e., under compression and torsion, on the induction and progression of IDD and its association with the Hippo-YAP/TAZ pathway. Therefore, bovine IVDs were assigned to one of four different static or complex dynamic loading regimes: (i) static, (ii) “low-stress”, (iii) “intermediate-stress”, and (iv) “high-stress” regime using a bioreactor. After one week of loading, a significant loss of relative IVD height was observed in the intermediate- and high-stress regimes. Furthermore, the high-stress regime showed a significantly lower cell viability and a significant decrease in glycosaminoglycan content in the tissue. Finally, the mechanosensitive gene CILP was significantly downregulated overall, and the Hippo-pathway gene MST1 was significantly upregulated in the high-stress regime. This study demonstrates that excessive torsion combined with compression leads to key features of IDD. However, the results indicated no clear correlation between the degree of IDD and a subsequent inactivation of the Hippo-YAP/TAZ pathway as a means of regenerating the IVD.

Morroniside attenuates nucleus pulposus cell senescence to alleviate intervertebral disc degeneration via inhibiting ROS-Hippo-p53 pathway

“…When the Hippo pathway is inactive, unphosphorylated Yap/Taz translocates into the nucleus and interacts with TEA-domain (Tead) transcription family (Tead1-4) to promote the transcription of target genes, including Cyr61, Ctgf, and Ankrd1 (Mo et al, 2014). Accruing works have shown that dysregulation of the Hippo pathway is involved in natural aging (Zhang et al, 2021b), excessive mechanical stress (Zhang et al, 2018a;Croft et al, 2021), or poly (methyl methacrylate) particles (Ge et al, 2019)-induced IVDD progression. Recent evidence from a tumor senescence study suggested that Taz, a core component and transcriptional coactivator of Hippo signaling, could negatively regulate p53 and attenuate p53-mediated cellular senescence (Miyajima et al, 2020), which repairs the NP senescent phenotype (Fearing et al, 2019) as well as osteoporosis and skeletal aging disease .…”

Pretreatment of nucleus pulposus mesenchymal stem cells with appropriate concentration of H2O2 enhances their ability to treat intervertebral disc degeneration

“…The Hippo pathway plays an important role in regulating stem cell proliferation and apoptosis [ 27 , 41 , 42 ]. Previous studies have shown that the activated Hippo pathway can inhibit cell proliferation and promote cell apoptosis of IVD cells [ 43 – 46 ]. Moreover, the inhibition of the Hippo pathway is closely related to H 2 O 2 -induced BMMSCs proliferation upregulation and apoptosis downregulation [ 47 ].…”

Immuno-Modulatory Effects of Intervertebral Disc Cells

“…Initial approaches were only capable of static loading; however, over time, bioreactors have gradually evolved to become more complex, incorporating diurnal loading ( Gantenbein et al, 2006 ) and dynamic compression ( Paul et al, 2012 ; Paul et al, 2013 ; Vergroesen et al, 2014 ). More recently, bioreactors have advanced past compression to include two- and six-dimensional degrees-of-freedom, allowing for the analysis of torsion, bending, flexion, and extension ( Costi et al, 2008 ; Chan et al, 2013 ; Croft et al, 2021 ). Additionally, asymmetrical complex loading has been proposed as a model to study the effects of scoliosis on disc mechanobiology ( Walter et al, 2011 ).…”