Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma

Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage

“…To test the function of vitamin C in glaucoma, we used the microbead occlusion model in 3-mo-old mice to induce unilateral elevated IOP. Because astrocytic SPP1 was found to be protective for RGCs and visual function ( Li & Jakobs, 2022 ), we then verified this effect in vivo by administering vitamin C (1%) to mice in the drinking water for 2 wk. Vitamin C up-regulated SPP1 protein expression in the intrinsically SPP1 + alpha ganglion cells in the retina and astrocytes in the optic nerve in glaucomatous mice in vivo ( Fig 4A and B ).…”

“…We recently reported that the cytokine-like protein SPP1 is highly protective of RGCs and visual function in several models of injury (elevated IOP, optic nerve crush, and aging) ( Li & Jakobs, 2022 ). In search of small molecules that can up-regulate SPP1 expression, we identified vitamins A (retinoic acid) and C that have been described to regulate SPP1 expression in osteoblast and other cell types ( Harada et al, 1995 ; Hadzir et al, 2014 ; Jeradi & Hammerschmidt, 2016 ; Nam et al, 2019 ).…”

“…Because Spp1 gene expression is regulated by transcription factors RUNX1 and E2F1 in astrocytes ( Li & Jakobs, 2022 ), we further sought to test whether these transcription factors are involved in the up-regulation of Spp1 by vitamin C. Sodium ascorbate up-regulated Spp1 and E2f1 , but not Runx1 , mRNA expression in cultured astrocytes ( Fig 1N ). The effect on Spp1 expression was dependent on E2F1, as it was blocked by the E2F1 inhibitor HLM006474 ( Fig 1O ).…”

“…We found previously that SPP1 induces a neuroprotective phenotype in astrocytes, including the inhibition of neurotoxic mediators, promotion of synaptogenic, phagocytic, and neurotropic markers, and an up-regulation of oxidative phosphorylation and ATP production ( Li & Jakobs, 2022 ). To further understand the molecular mechanism of vitamin C activity in astrocytes, we used qRT-PCR to test whether vitamin C could also induce neuroprotective astrocytes by regulating these pathways via SPP1.…”

“…We recently found that the overexpression of the cytokine SPP1 (secreted phosphoprotein 1, osteopontin) in the retina and optic nerve head protects RGCs and rescues visual function in mouse models of aging and glaucoma ( Li & Jakobs, 2022 ). We sought to screen and identify small molecules that increase SPP1 expression as an adjuvant glaucoma treatment.…”