Scleral hypoxia and myopia

In my post Red light therapy for myopia control, I came across the concept of a potential mechanism for myopia control. Scleral hypoxia. Though my knowledge of molecular biology is significantly lacking. I found the results and discussion of these pathways utterly fascinating. I read through two papers: Scleral Mechanisms Underlying Ocular Growth and Myopia published in the June 2015 issue of Progress in Molecular Biology and Translational Science and Scleral Hypoxia Is a Target for Myopia Control in the July 2018 issue of PNAS.

The 2015 paper gives a good background to the 2018 one. It discusses potential mechanisms of why the eye grows in such a runaway fashion in myopia.

The sclera is predominantly made up of collagen, with interspersed fibroblasts that produce and maintain its extracellular matrix

The biomechanical makeup of the myopic sclera can in turn affect the lamina cribrosa which might be the reason for increased risk of glaucoma in myopes.

its glycosaminoglycan and collagen contents are reduced and its fibril assembly disorganized, rendering it biomechanically weaker

I won’t list all the potential mechanisms that fouls up collagen to create a myopic eye. However, I will point out one inconsistency. They reference a study that found that cyclic AMP (cAMP) and cyclic GMP (cGMP) were found in increased concentrations in myopic scleras. Later on, though, they say that in Denmark oral 7-methylxanthine is an approved treatment for myopia control. Methylxanthines (theophylline is the most common) are used in non-obstructive lung diseases. One of the mechanisms of action of this class of drug is that is inhibits the phosphodiesterase enzyme which increases levels of cAMP and cGMP. How can a drug that increases this inhibit myopia? 🤷‍♂️

Anyway, moving on to the scleral hypoxia paper.

The identification of the scleral hypoxia in myopia not only provides a concept for understanding the mechanisms of myopia development but also suggests viable therapeutic approach to control myopia progression in humans.

They narrowed it down to hypoxia-inducible factor-1⍺ (HIF-1⍺) which promotes myofibroblast transdifferentiation. This leads to down-regulation of type I collagen.

type I collagen is the major scleral ECM component, and declines in its expression weaken the scleral structural framework. During myopia development, type I collagen turnover increases due to down-regulation of its synthesis along with increased degradation

They found that two different antihyopxia drugs, salidroside and formononetin, significantly limited myopia formation in mice. These drugs significantly inhibit HIF-1α formation. The main question is why does the eye create an hypoxic environment for myopia to develop.

There has been speculation that there are signals from the retina (maybe hyperopic defocus) which produce mediators to allow for HIF-1α increases which causes myofibroblast transdifferentiation. This weaken the extracellular matrix of the scleral causing it to grow abnormally.

This paper is very dense, and I’m going to be going over it a few more times, but I urge you to read it. It goes in depth of effects of the choroid that my writing cannot do justice. I will leave you with this.

muscarinic receptor antagonists, such as atropine, that slow the clinical progression of myopia also suppress myopia progression and choroidal thinning in chicks, suggesting that they might also act through amelioration of scleral hypoxia

Lots to chew on in this paper. Inching ever closer to a real treatment for myopia.