Figure 14.

CH phenotype regulation, e.g., in OA or through serial passaging, pro-inflammatory cytokines, and/or growth factors control CH function through SF formation and the actin-regulating signaling pathways RhoA/ROCK/Rac1/mDia1/mDia2/Cdc42. SF formation in CHs induces a dedifferentiated fibroblastic morphology, a fibrogenic (increased COL1 and COL3 expression) and catabolic (formation of COL2 and aggrecan fragments) phenotype, and increased COL1 expression, induced by the nuclear localization of MRTF. This review theorized that in CHs phosphorylation of SOX9 (and subsequently increased COL2 expression as chondrogenic phenotype marker) by ROCK is effectively sidelined in favor of other SF promoting ROCK substrates (LIMK2, ezrin, and MLC), based on a differential affinity of various ROCK substrates, explaining how it is molecularly possible that dedifferentiation induces low COL2 expression but high SF formation. Abbreviations: COL1: type I collagen, COL2: type II collagen, COL3: type III collagen, IL-1α: interleukin 1α, IL-1β: interleukin 1β, IL-6: interleukin 6, IL-8: interleukin 8, MRTF: myocardin-related transcription factor, ROCK: Rho-kinase, SOX9: SRY-box transcription factor 9, TGF-α: transforming growth factor α, TNF-α: tumor necrosis factor α. The up and down arrows indicate an increase or decrease.