Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss


In fibrous tissues, prestressed boundary constraints at bone interfaces instil residual strain throughout the tissue, even when unloaded. For example, internal swelling pressures in the central nucleus pulposus of the intervertebral disc generate prestrain in the outer annulus fibrosus. With injury and depressurization, these residual strains are lost. Here we show that the loss of residual strains in the intervertebral disc alters the microenvironment and instigates aberrant tissue remodelling and the adoption of atypical cellular phenotypes. By using puncture surgery of the annulus fibrosus in rabbits, ex vivo puncture experiments and electrospun nanofibrous scaffolds recapitulating these evolving boundary constraints, we show that the loss of residual strain promotes short-term apoptosis and the emergence of a fibrotic phenotype. We also show that local fibre organization and cellular contractility mediate this process and that the aberrant cellular changes could be abrogated by targeting the cell-mechanosensing machinery with small molecules. Our findings indicate that injury to dense connective tissues under prestrain alters boundary constraints and residual strain; this leads to aberrant mechanosensing, which in turn promotes disease progression.

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Fig. 1: In vivo disc puncture and release of residual strains alters mechanics and initiates aberrant remodelling of the disc.
Fig. 2: Scaffold-based system to evaluate the impact of prestrain in fibrous microenvironments.
Fig. 3: Boundary conditions and fibre organization govern cell spreading and mechanosensation.
Fig. 4: Local fibre organization mediates AF cell phenotype and biosynthetic response.
Fig. 5: In vitro disc puncture releases residual strain, altering fibre morphology and disc mechanics and triggering apoptosis.
Fig. 6: Cells respond differently to stretch and release of tension.
Fig. 7: Disc injury initiates altered mechanosensing leading to soft tissue degeneration.

Data availability

The main data supporting the results in this study are available in the Article and Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request.


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This study was supported by the United States National Institutes of Health (grant nos. F32 AR072478, R01 EB02425, T32 AR053461 and P30 AR050950), the United States Department of Veteran’s Affairs (grant nos. I01 RX002274 and IK1 RX002445), the Ministry of Science and Technology, Taiwan (grant nos. MOST107-2918-I-002-024 and MOST107-2221-E-002-071-MY2) and the Taiwan National Health Research Institute (grant no. NHRI-EX107-10411EI). Additional support was provided by the Unites States National Science Foundation via the NSF Science and Technology Center for Engineering Mechanobiology (grant no. CMMI-1548571). The authors thank D. Mason and J. Boerkel for their assistance with traction force microscopy and C. Loebel and J. Burdick for their assistance with FUNCAT labelling of nascent matrix.

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E.D.B., H.E.S., D.M.E. and R.L.M. conceived and designed the experiments. E.D.B., S.E.G., B.G.A., T.K.T., P.G.C. and H.E.S. performed the experiments. E.D.B., S.E.G. and B.G.A. analysed the data. T.K.T. and P.G.C. contributed materials/analysis tools. E.D.B. and R.L.M. wrote the manuscript. E.D.B., S.E.G., B.G.A., T.K.T., D.M.E., P.G.C., H.E.S. and R.L.M. edited the manuscript.

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Correspondence to Robert L. Mauck.

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Calcium transients on cells seeded on scaffolds.

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Calcium transients on cells seeded on scaffolds.

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Bonnevie, E.D., Gullbrand, S.E., Ashinsky, B.G. et al. Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss. Nat Biomed Eng 3, 998–1008 (2019). https://doi.org/10.1038/s41551-019-0458-4

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