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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Dec 24

PMID 34948441

Citations 7

Authors

Andreas S Croft

Ysaline Roth

Katharina A C Oswald

Slavko Corluka

Paola Bermudez-Lekerika

Benjamin Gantenbein

Affiliations

Soon will be listed here.

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 was significantly downregulated overall, and the Hippo-pathway gene 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.

Citing Articles

Ex Vivo and In Vitro Proteomic Approach to Elucidate the Relevance of IL-4 and IL-10 in Intervertebral Disc Pathophysiology.

Bermudez-Lekerika P, Tseranidou S, Kanelis E, Nuesch A, Crump K, Alexopoulos L JOR Spine. 2025; 8(1):e70048.

PMID: 39931581 PMC: 11808320. DOI: 10.1002/jsp2.70048.

Role of YAP/TAZ in bone diseases: A transductor from mechanics to biology.

Chen X, Ji X, Lao Z, Pan B, Qian Y, Yang W J Orthop Translat. 2025; 51:13-23.

PMID: 39902099 PMC: 11787699. DOI: 10.1016/j.jot.2024.12.003.

The Role of the Bone Morphogenetic Protein Antagonist Noggin in Nucleus Pulposus Intervertebral Disc Cells.

Chen S, Bigdon S, Riether C, Ma X, Niu X, Hackel S Int J Mol Sci. 2024; 25(21).

PMID: 39519354 PMC: 11546912. DOI: 10.3390/ijms252111803.

Repetitive strikes loading organ culture model to investigate the biological and biomechanical responses of the intervertebral disc.

Zhou J, Wang J, Li J, Zhu Z, He Z, Li J JOR Spine. 2024; 7(1):e1314.

PMID: 38249719 PMC: 10797252. DOI: 10.1002/jsp2.1314.

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

Zhou C, Yao S, Fu F, Bian Y, Zhang Z, Zhang H Front Pharmacol. 2022; 13:942435.

PMID: 36188539 PMC: 9524229. DOI: 10.3389/fphar.2022.942435.

References

Wong M, Siegrist M, Cao X . Cyclic compression of articular cartilage explants is associated with progressive consolidation and altered expression pattern of extracellular matrix proteins. Matrix Biol. 1999; 18(4):391-9. DOI: 10.1016/s0945-053x(99)00029-3. View

Patel K, Sandy J, Akeda K, Miyamoto K, Chujo T, An H . Aggrecanases and aggrecanase-generated fragments in the human intervertebral disc at early and advanced stages of disc degeneration. Spine (Phila Pa 1976). 2007; 32(23):2596-603. DOI: 10.1097/BRS.0b013e318158cb85. View

Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N . A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell. 2013; 154(5):1047-1059. DOI: 10.1016/j.cell.2013.07.042. View

Oichi T, Taniguchi Y, Oshima Y, Tanaka S, Saito T . Pathomechanism of intervertebral disc degeneration. JOR Spine. 2020; 3(1):e1076. PMC: 7084053. DOI: 10.1002/jsp2.1076. View

Heidary Arash E, Shiban A, Song S, Attisano L . MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells. EMBO Rep. 2017; 18(3):420-436. PMC: 5331264. DOI: 10.15252/embr.201642455. View

Zhao B, Wei X, Li W, Udan R, Yang Q, Kim J . Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007; 21(21):2747-61. PMC: 2045129. DOI: 10.1101/gad.1602907. View

Vergroesen P, Kingma I, Emanuel K, Hoogendoorn R, Welting T, van Royen B . Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthritis Cartilage. 2015; 23(7):1057-70. DOI: 10.1016/j.joca.2015.03.028. View

Frauchiger D, Chan S, Benneker L, Gantenbein B . Intervertebral disc damage models in organ culture: a comparison of annulus fibrosus cross-incision versus punch model under complex loading. Eur Spine J. 2018; 27(8):1785-1797. DOI: 10.1007/s00586-018-5638-5. View

Roberts S, Evans H, Trivedi J, Menage J . Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am. 2006; 88 Suppl 2:10-4. DOI: 10.2106/JBJS.F.00019. View

10.

Walter B, Korecki C, Purmessur D, Roughley P, Michalek A, Iatridis J . Complex loading affects intervertebral disc mechanics and biology. Osteoarthritis Cartilage. 2011; 19(8):1011-8. PMC: 3138834. DOI: 10.1016/j.joca.2011.04.005. View

11.

Harvey K, Pfleger C, Hariharan I . The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell. 2003; 114(4):457-67. DOI: 10.1016/s0092-8674(03)00557-9. View

12.

Zhou Z, Cui S, Du J, Geoff Richards R, Alini M, Grad S . One strike loading organ culture model to investigate the post-traumatic disc degenerative condition. J Orthop Translat. 2021; 26:141-150. PMC: 7773974. DOI: 10.1016/j.jot.2020.08.003. View

13.

Chen C, Gajewski K, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C . The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A. 2010; 107(36):15810-5. PMC: 2936591. DOI: 10.1073/pnas.1004060107. View

14.

Sambrook P, MacGregor A, Spector T . Genetic influences on cervical and lumbar disc degeneration: a magnetic resonance imaging study in twins. Arthritis Rheum. 1999; 42(2):366-72. DOI: 10.1002/1529-0131(199902)42:2<366::AID-ANR20>3.0.CO;2-6. View

15.

Kerttula L, Serlo W, Tervonen O, Paakko E, Vanharanta H . Post-traumatic findings of the spine after earlier vertebral fracture in young patients: clinical and MRI study. Spine (Phila Pa 1976). 2000; 25(9):1104-8. DOI: 10.1097/00007632-200005010-00011. View

16.

Chan E, Nousiainen M, Chalamalasetty R, Schafer A, Nigg E, Sillje H . The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene. 2005; 24(12):2076-86. DOI: 10.1038/sj.onc.1208445. View

17.

Adams M, Roughley P . What is intervertebral disc degeneration, and what causes it?. Spine (Phila Pa 1976). 2006; 31(18):2151-61. DOI: 10.1097/01.brs.0000231761.73859.2c. View

18.

Brinckmann P, Grootenboer H . Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs. Spine (Phila Pa 1976). 1991; 16(6):641-6. DOI: 10.1097/00007632-199106000-00008. View

19.

Shiri R, Karppinen J, Leino-Arjas P, Solovieva S, Viikari-Juntura E . The association between smoking and low back pain: a meta-analysis. Am J Med. 2010; 123(1):87.e7-35. DOI: 10.1016/j.amjmed.2009.05.028. View

20.

Illien-Junger S, Gantenbein-Ritter B, Grad S, Lezuo P, Ferguson S, Alini M . The combined effects of limited nutrition and high-frequency loading on intervertebral discs with endplates. Spine (Phila Pa 1976). 2010; 35(19):1744-52. DOI: 10.1097/BRS.0b013e3181c48019. View