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.

近视是全世界视力屈光不正的最常见原因。环磷酸腺苷 (cAMP) 连接的信号通路有助于调节近视发展，cAMP 积累的增加促进近视进展。为了查明 cAMP 调节近视进展的潜在机制，我们在缺乏形态的小鼠中进行了巩膜转录组测序分析，这是一种完善的近视发展模型。形式剥夺显着抑制了 cAMP 分解代谢途径中基因的表达水平。定量实时聚合酶链反应分析证实磷酸二酯酶 4B ( PDE4B )（一种 cAMP 水解酶）的基因表达水平在形态剥夺的小鼠眼中被下调。在视觉无障碍的情况下，损失Pde4b基因敲除小鼠中的PDE4B功能增加了屈光度的近视偏移，-3.661 ± 1.071 屈光度，超过Pde4b野生型同窝仔鼠（P  < 0.05）。这表明PDE4B 的下调和抑制导致近视。在豚鼠中，结膜下注射 PDE4 的选择性抑制剂咯利普兰会导致正常眼睛的近视，并且还会增强形式剥夺性近视 (FDM)。结膜下注射二丁酰环磷酸腺苷（一种 cAMP 类似物）仅在正常视力无障碍的眼睛中引起近视移位，但不会增强 FDM。随着近视的发展，巩膜重塑期间发生轴向伸长，这与胶原纤维厚度和分布的变化相关。FDM + 咯利普兰组的中位胶原纤维直径为 55.09 ± 1.83 nm，比 FDM + 赋形剂组的 59.33 ± 2.06 nm ( P = 0.011）。因此，相对于形式剥夺眼中的载体治疗，用咯利普兰抑制 PDE4 活性使胶原原纤维直径变薄。咯利普兰还抑制培养的人巩膜成纤维细胞中由 TGF-β2 诱导的胶原合成增加。目前的结果进一步支持 PDE 酶（如 PDE4B）在调节正常屈光发育和近视中的作用，因为 PDE4B 功能的丧失或抑制会通过巩膜胶原纤维直径的下降增加近视和 FDM 的发展。