In situ cell signalling of the hippo-YAP/TAZ pathway in reaction to complex dynamic loading in an intervertebral disc

Croft, Andreas S.; Roth, Ysaline; Oswald, Katharina A. C.; Corluka, Slavko; Bermudez-Lekerika, Paola; Gantenbein, Benjamin (2021). In situ cell signalling of the hippo-YAP/TAZ pathway in reaction to complex dynamic loading in an intervertebral disc (Unpublished). In: 29th annual meeting of the European Orthopaedic Research Society. Rome, Italy. 14-18 september.

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Introduction: Intervertebral disc (IVD) degeneration (IDD) is a main contributor to chronic low back pain. Recently, a dysregulation of the Hippo-YAP/TAZ pathway has been correlated with IDD, as it plays a key role in cell proliferation, differentiation, regeneration, and cell survival. Therefore, our aim was to investigate the influence of different mechanical loading profiles in two Degree-of-Freedom (2DoF) loading, i.e., under compression and torsion, on the induction and progression of IDD and in particularly the role and context of the Hippo-YAP/TAZ pathway.

Methods: Around one-year old coccygeal IVDs were isolated from bovine tails obtained from a local abattoir. All IVDs were excised and prepared for organ culture as previously established and then randomly assigned to one of four different static or complex mechanical loading regimes for seven days, i.e., i) “static” (0.1 MPa compression), ii) “low stress” (up to 0.2 MPa compression and 2° torsion), iii) “intermediate stress” (up to 0.4 MPa compression and 8° torsion), and iv) “high stress” (up to 0.6 MPa compression and 15° torsion) profile using a bioreactor that allows 2DoF loading. After one week of loading, the tissue and the culture medium of each condition was harvested and analysed for their glycosaminoglycan (GAG) content, relative disc height changes, relative gene expression of anabolic, catabolic, and inflammatory markers, as well as the major players in the Hippo-YAP/TAZ pathway.

Results: After one week of organ culture, a significant loss of IVD height was observed in every mechanical loading regime, with the most significant height loss observed in the higher stress regimes (up to 27 ± 5% height loss). Furthermore, the high stress condition showed a significant decrease of GAG in the tissue (232 ± 48 vs. up to 314 ± 14 µg GAG / mg dry weight) and a significant increase of GAG in the culture medium (97 ± 14 vs. 44 ± 22 µg GAG / cm3 freshly isolated tissue). Moreover, a higher upregulation of catabolic (MMP13 up to 1805 ± 2284-fold upregulation) and inflammation-related genes (MCP1 up to 121 ± 201-fold upregulation) was generally observed the more stressed the IVDs were. Finally, a significant upregulation of TAZ (up to 49 ± 73-fold upregulation) was found for the high stress condition.

Conclusion: Altogether, this study demonstrated that excessive torsion combined with compression leads to key features of IDD. Furthermore, we were able to show that the Hippo-YAP/TAZ pathway reacted differently depending on the applied mechanical loading profile and the degenerated state of the IVD. Hence, this study showed the potential of targeting the Hippo-YAP/TAZ pathway to counteract IDD.

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