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 3 beta (GSK3 beta), an enzyme with pleiotropic effects in osteoarthritis. A dysfunctional TRPV4-GSK3 beta 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. A dysfunctional TRPV4-GSK3 beta pathway in osteoarthritic chondrocytes renders the cells unable to respond to viscoelastic changes in the extracellular matrix.

Automated summary

The viscoelasticity of alginate hydrogels regulates cell volume in healthy chondrocytes but not in osteoarthritic chondrocytes. This difference in response is associated with changes in anabolic gene expression, secretion of pro-inflammatory cytokines, and modulation of intracellular calcium. Dysfunctional TRPV4-GSK3 beta pathway in osteoarthritic chondrocytes renders them unable to respond to viscoelastic changes in the extracellular matrix.