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.