Hydrostatic Pressure Modulates Intervertebral Disc Cell Survival and Extracellular Matrix Homeostasis via Regulating Hippo-YAP/TAZ Pathway

Abstract

Established studies proved that hydrostatic pressure had multiple effects on the biological behavior of the intervertebral disc (IVD). However, the conclusions of the previous studies were inconsistent, due to the difference in hydrostatic loading devices and observing methods used in these studies. The current study is aimed at investigating the role of dynamic hydrostatic pressure in regulating biological behavior of the notochordal nucleus pulposus (NP) and fibrocartilaginous inner annulus fibrosus (AF) and its possible mechanism using our novel self-developed hydrostatic pressure bioreactor. The differences in the biological behavior of the rabbit IVD tissues under different degree of hydrostatic pressure were evaluated via histological analysis. Results revealed that low-loading dynamic hydrostatic pressure was beneficial for cell survival and extracellular matrix (ECM) homeostasis in notochordal NP and fibrocartilaginous inner AF via upregulating N-cadherin (N-CDH) and integrin β1. In comparison, high-magnitude dynamic hydrostatic pressure aggravated the breakdown of ECM homeostasis in NP and inner AF via enhancing the Hippo-YAP/TAZ pathway-mediated cell apoptosis. Moreover, inner AF exhibited greater tolerance to physiological medium-loading degree of hydrostatic pressure than notochordal NP. The potential mechanism was related to the differential expression of mechanosensing factors in notochordal NP and fibrocartilaginous inner AF, which affects the fate of the cells under hydrostatic pressure. Our findings may provide a better understanding of the regulatory role of hydrostatic pressure on the cellular fate commitment and matrix metabolism of the IVD and more substantial evidence for using hydrostatic pressure bioreactor in exploring the IVD degeneration mechanism as well as regeneration strategies.

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

“…A similar study on the influence of different hydrostatic pressure intensities on the endogenous YAP regulation and the ECM turnover of rabbit IVDs was carried out by Wang et al [53]. There, significant differences in the proteomic YAP expression were only found at a minimal pressure of 0.8 MPa in the NP and 1.0 MPa in the AF, both of which are higher than any of the pressures that were applied in our study.…”

Dynamic Pressure Stimulation Upregulates Collagen II and Aggrecan in Nucleus Pulposus Cells Through Calcium Signaling

“…31 In addition, TRPA1 agonist allyl isothiocyanate were found to regulate gene expression of Collagen II in NP, 32 linking the activation of TRP channels to regulation of ECM proteins. Given that dynamic pressure simulation was known to regulate ECM protein production, 33 our results offered evidence for the novel annotation of TRP as being sensitive to pressure fluctuation, and serving as the link between mechanotransduction and ECM protein production. The upregulation of Collagen II by dynamic stimulation might create additional benefits due to the piezoelectric effect.…”

Intervertebral Disc-on-a-Chip as Advanced In Vitro Model for Mechanobiology Research and Drug Testing: A Review and Perspective

“…Interestingly, ROCK inhibition abolished cell-cell interactions and the formation of clusters in NP cells (Hwang et al, 2014). Cytoskeletal regulation of NP and AF cells has further been associated with the yes-associated protein (YAP) and transcriptional coactivator PDZ-binding motif (TAZ) signaling (Fearing et al, 2019;Wang et al, 2021). Cytoskeletal reorganization mediated by F-actin remodeling occurs also in response to hypo-and hyper-osmolarity resulting in cell volume changes (Fearing et al, 2018).…”