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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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.).
The authors declare no competing interests.
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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). https://doi.org/10.1038/s41551-021-00691-3