**4. Retinoic acid on scleral proteoglycan synthesis**

The retina, choroid and sclera are three possible tissue targets for choroidally generated atRA within the eye. Of these three targets, the sclera is a leading candidate. Based on results using a specific inhibitor of proteoglycan synthesis

**Figure 2.** 

*Choroidal retinoic acid synthesis and scleral proteoglycan synthesis during recovery from form deprivation myopia. (A) Changes in choroidal all-trans-retinoic acid (atRA) synthesis during recovery from experimental myopia. (B) Changes in scleral proteoglycan synthesis in during recovery from experimental myopia. A from: Mertz and Wallman [9]. B adapted from: Summers and Hollaway [53]. Reproduced with permission © Elsevier.* 

 (*p*-nitrophenyl-beta-d-xylopyranoside), we previously demonstrated that the rate of proteoglycan synthesis in the cartilaginous layer of the chick sclera is largely responsible for visually guided changes in eye size [27, 52]. Moreover, proteoglycan synthesis is rapidly upregulated in the sclera in response to visual form deprivation and is rapidly downregulated in the posterior sclera to levels significantly below those of fellow controls within 12 hours upon restoration of unrestricted vision (=recovery from induced myopia) [53, 54]. Interestingly, the time course of the increase in choroidal atRA synthesis during recovery from induced myopia [9] was remarkably similar to that of the decrease in rate of sclera proteoglycan synthesis observed in the early phase of recovery from induced myopia [53] suggesting a causal relationship between choroidal atRA synthesis and scleral proteoglycan synthesis (**Figure 2**). Moreover, *RALDH2* mRNA pools in the chick choroid were shown to increase and decrease in a manner that inversely correlated with changes in scleral proteoglycan synthesis in recovering eyes [10], suggesting that RALDH2 gene expression in the choroid regulate choroidal atRA synthesis during visually induced ocular growth. It is well known that atRA is a potent inhibitor of proteoglycan biosynthesis by chondrocytes [55, 56] and that it facilitates cartilage catabolism through the increased synthesis of matrix-degrading enzymes [55, 57, 58]. atRA inhibits scleral proteoglycan synthesis in a dose-dependent manner with an IC50 of 8 × 10<sup>−</sup><sup>9</sup> M, which is similar to the measured endogenous levels of atRA in choroid organ cultures (4 × 10<sup>−</sup><sup>9</sup> to 7 × 10<sup>−</sup><sup>9</sup> M) [10]. At this concentration, atRA would be able to regulate scleral growth matrix remodeling through the stimulation or repression of transcription factors, extracellular matrix constituents, and MMPs or TIMPs.
