Calcitriol attenuates form-deprivation myopia through VDR-mediated inhibition of NF-κB signaling and scleral remodeling.

PURPOSE: To investigate the role and mechanisms of calcitriol in form-deprivation myopia (FDM).

METHODS

Calcitriol was evaluated in a guinea pig FDM model and a tumor necrosis factor-alpha (TNF-α)-induced inflammatory model using human retinal pigment epithelial (RPE) cells. Vitamin D receptor (VDR) dependence was assessed by adeno-associated virus- or small interfering RNA-mediated VDR knockdown. Refractive status, axial length, fundus changes, scleral collagen remodeling, inflammatory cytokines, nuclear factor kappa-B (NF-κB) activation, and matrix metalloproteinase-2 (MMP2) expression were examined. Protein interaction analysis explored VDR-NF-κB p65 interaction.

RESULTS

Calcitriol significantly attenuated FDM progression in guinea pigs, reducing myopic refractive shift, axial elongation, and fundus alterations. It increased scleral collagen expression and improved collagen organization and ultrastructure. Calcitriol also decreased circulating and retinal TNF-α, interleukin-1β, and interleukin-6 levels, accompanied by NF-κB inhibition and MMP2 downregulation. VDR knockdown markedly weakened the protective effects of calcitriol on refractive and axial changes, inflammatory cytokine production, and NF-κB/MMP2 signaling. In vitro, calcitriol inhibited TNF-α-induced NF-κB p65 nuclear translocation and reduced inflammatory cytokine secretion and MMP2 expression in RPE cells; these effects were largely abolished by VDR knockdown. Protein interaction analysis suggested that calcitriol enhanced VDR-NF-κB p65 interaction, thereby restricting NF-κB activation.

CONCLUSIONS

Calcitriol delays FDM progression through VDR-mediated inhibition of NF-κB activation, reducing inflammatory cytokine production, MMP2 expression, scleral collagen degradation, and tissue remodeling.