Declines in PDE4B activity promote myopia progression through downregulation of scleral collagen expression. (November 2021)

• Record Type: Journal Article
• Authors: Zhao, Fuxin; Zhou, Hui; Chen, Wei; Zhao, Chenchen; Zheng, Yangyang; Tao, Yijin; Pan, Miaozhen; Reinach, Peter S.; Zhu, Jiadi; An, Jianhong; Lu, Runxia; Chen, Jiang-fan; Tang, Huifang; Zeng, Changqing; Qu, Jia; Zhou, Xiangtian
• Is Part Of: Experimental eye research. Volume 212(2021)
• Publication Date: 2021-11
• Subjects: Phosphodiesterase 4B (PDE4B) -- Myopia -- Form-deprivation myopia (FDM) -- Pde4b-knockout mice -- Rolipram -- Collagen; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2021.108758
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Myopia is the most common cause of a visual refractive error worldwide. Cyclic adenosine monophosphate (cAMP)-linked signaling pathways contribute to the regulation of myopia development, and increases in cAMP accumulation promote myopia progression. To pinpoint the underlying mechanisms by which cAMP modulates myopia progression, we performed scleral transcriptome sequencing analysis in form-deprived mice, a well-established model of myopia development. Form deprivation significantly inhibited the expression levels of genes in the cAMP catabolic pathway. Quantitative real-time polymerase chain reaction analysis validated that the gene expression level of phosphodiesterase 4B ( PDE4B ), a cAMP hydrolase, was downregulated in form-deprived mouse eyes. Under visually unobstructed conditions, loss of PDE4B function in Pde4b -knockout mice increased the myopic shift in refraction, −3.661 ± 1.071 diopters, more than that in the Pde4b -wildtype littermates ( P < 0.05). This suggests that downregulation and inhibition of PDE4B gives rise to myopia. In guinea pigs, subconjunctival injection of rolipram, a selective inhibitor of PDE4, led to myopia in normal eyes, and it also enhanced form-deprivation myopia (FDM). Subconjunctival injection of dibutyryl-cyclic adenosine monophosphate, a cAMP analog, induced only a myopic shift in the normal visually unobstructed eyes, but it did not enhance FDM. As myopia developed, axial elongation occurred during scleral remodeling that was correlated with changes in collagen fibril thickness and distribution. The median collagen fibril diameter in the FDM + rolipram group, 55.09 ± 1.83 nm, was thinner than in the FDM + vehicle group, 59.33 ± 2.06 nm ( P = 0.011). Thus, inhibition of PDE4 activity with rolipram thinned the collagen fibril diameter relative to the vehicle treatment in form-deprived eyes. Rolipram also inhibited increases in collagen synthesis induced by TGF-β2 in cultured human scleral fibroblasts. The current results further support a role for PDE enzymes such as PDE4B in the regulation of normal refractive development and myopia because either loss or inhibition of PDE4B function increased myopia and FDM development through declines in the scleral collagen fibril diameter. Highlights: ● Pde4b mRNA expression was downregulated in form-deprived eyes of mice ● Pde4b knockout leads to a refraction shift towards myopia in mice ● Inhibition of PDE4B by rolipram leads to myopia in normal guinea pig eyes and enhances form deprivation myopia ● Inhibition of PDE4B with rolipram thins the scleral collagen fibril diameter in form-deprived eyes ● PDE4B is an important gene involved in modulating myopia progression through suppression of scleral collagen