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A dysfunctional TRPV4–GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity


Changes in the composition and viscoelasticity of the extracellular matrix in load-bearing cartilage influence the proliferation and phenotypes of chondrocytes, and are associated with osteoarthritis. However, the underlying molecular mechanism is unknown. Here we show that the viscoelasticity of alginate hydrogels regulates cellular volume in healthy human chondrocytes (with faster stress relaxation allowing cell expansion and slower stress relaxation restricting it) but not in osteoarthritic chondrocytes. Cellular volume regulation in healthy chondrocytes was associated with changes in anabolic gene expression, in the secretion of multiple pro-inflammatory cytokines, and in the modulation of intracellular calcium regulated by the ion-channel protein transient receptor potential cation channel subfamily V member 4 (TRPV4), which controls the phosphorylation of glycogen synthase kinase 3β (GSK3β), an enzyme with pleiotropic effects in osteoarthritis. A dysfunctional TRPV4–GSK3β pathway in osteoarthritic chondrocytes rendered the cells unable to respond to environmental changes in viscoelasticity. Our findings suggest strategies for restoring chondrocyte homeostasis in osteoarthritis.

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Fig. 1: Normal chondrocytes exhibit a robust response to differential stress relaxation with changes in volume, gene expression and secreted factors.
Fig. 2: Slow ECM stress relaxation primes normal chondrocytes for an elevated response to inflammatory cues.
Fig. 3: Intracellular-calcium-dependent changes in cellular signalling landscape in normal chondrocytes.
Fig. 4: Activation of TRPV4 leads to increased intracellular calcium levels, GSK3β phosphorylation and inflammatory phenotype.
Fig. 5: Inhibition of TRPV4 leads to decreased intracellular calcium levels, GSK3β phosphorylation and reduced inflammatory phenotype.
Fig. 6: Response to viscoelasticity is absent in OA chondrocytes.
Fig. 7: OA chondrocytes do not regulate intracellular calcium through TRPV4, leading to chronic high GSK3β and inflammation.
Fig. 8: Matrix viscoelasticity is transduced to chondrocytes via the TRPV4–GSK3β axis in normal cartilage but not OA cartilage.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets are available in figshare with the identifier (ref. 76).


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We thank Y. Rosenberg-Hasson at the Stanford Human Immune Profiling Center for help with the Luminex analysis. These studies were supported by funding from the Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program (IIP) (R9-52 to N.B. and O.C.), National Institutes of Health grants (R01 AR070864 and R01 AR070865 to N.B. and R21 AR074070 to O.C.) and a Stanford Bio-X fellowship (to H.-p.L.).

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P.A., H.-p.L., O.C. and N.B. designed the overall study. P.A. and H.-p.L. conducted experiments and analysed the data. P.S. and F.G. contributed to discussions and data interpretation. S.G. provided samples from human patients with OA. P.A., H.-p.L., O.C. and N.B. wrote the manuscript.

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Correspondence to Ovijit Chaudhuri or Nidhi Bhutani.

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Agarwal, P., Lee, Hp., Smeriglio, P. et al. A dysfunctional TRPV4–GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity. Nat Biomed Eng (2021).

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