Gap junction–independent mechanisms of Cx43 under carbenoxolone treatment

Determine whether connexin43 mediates gap junction–independent mechanisms that contribute to the phenotypic switching and redifferentiation observed in osteoarthritic chondrocytes treated with the gap junction inhibitor carbenoxolone, beyond effects attributable to gap junction–dependent signaling.

Background

The study shows that inhibiting gap junctional intercellular communication (GJIC) with carbenoxolone (CBX) promotes redifferentiation of osteoarthritic chondrocytes and reduces inflammatory mediators. However, CBX also decreases Cx43 protein levels, raising uncertainty about whether the observed effects are solely mediated through GJ-dependent pathways.

Disentangling gap junction–dependent from potential gap junction–independent roles of Cx43 in chondrocyte phenotypic control is necessary to precisely target therapeutic strategies that modulate Cx43 or GJIC in OA.

References

Together, our results on the inhibition of dye transfer and downregulation of Cx43 in CBX-treated chondrocytes suggest that chondrocyte redifferentiation observed upon CBX treatment occurred through a GJ-dependent manner (Cx43 plaques). However it is difficult to exclude Cx43 GJ-independent mechanisms in these phenotypic switching because CBX also reduced the levels of Cx43.

— Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis  (2402.00624 - Varela-Eirin et al., 2024) in Discussion, page 8