Collagen Gene Expression and the Altered Accumulation of Scleral Collagen during the Development of High Myopia

Abstract

The development of high myopia is associated with reduced scleral collagen accumulation, scleral thinning, and loss of scleral tissue, in both humans and animal models. Reduced collagen fibril diameter is also observed in the sclera of eyes with high myopia. The present study investigated aspects of scleral collagen synthesis and degradation, in a mammalian model of high myopia, to elucidate the factors underlying scleral changes. General synthesis and degradation of scleral collagen was investigated in monocularly deprived tree shrews, through the in vivo administration of [ 3 H]proline and subsequent assay of scleral tissue for [ 3 H]collagen. In addition, PCR enriched cDNA, produced from tree shrew scleral mRNA, was used to synthesize probes for hybridization to custom gene arrays consisting of partial sequences for 11 collagen subtypes. Finally, realtime reverse transcriptase-PCR was employed to investigate collagen type I, III, and V mRNA expression in the sclera of myopic, contralateral control, and normal tree shrew eyes. Scleral [ 3 H]proline incorporation was reduced at the posterior pole of myopic eyes following 5 days of monocular deprivation (؊36 ؎ 4%), whereas [ 3 H]proline content was similar in treated and control eyes before myopia induction (؊1 ؎ 8%) but was reduced in myopic eyes following 5 (؊8 ؎ 2%), 12 (؊15 ؎ 4%), and 24 (؊10 ؎ 4%) days of myopia induction. The majority of the collagens investigated were found to be expressed in the sclera, with 11 subtypes being identified. Collagen type I mRNA expression was reduced in the sclera of myopic eyes (؊20 ؎ 7%), however, collagen type III (؉2 ؎ 9%) and type V (؊1 ؎ 6%) expression was unchanged relative to control, resulting in a net increase in the ratio of expression of collagen type III/type I and collagen type V/type I (22 and 25%, respectively). These results show that reduced scleral collagen accumulation in myopic eyes is a result of both decreased collagen synthesis and accelerated collagen degradation. Furthermore, changes in collagen synthesis are driven by reduced type I collagen production. Short term increases in the ratio of newly synthesized collagen type III/type I and type V/type I are likely to be important in the increasing frequency of small diameter scleral collagen fibrils observed in high myopia and may be important in the subsequent development of posterior staphyloma in humans with pathological myopia.The refractive power of the eye is correlated with ocular axial length and it is well established that myopia is caused by increased axial eye size (1). Studies, in humans and animal models, have shown how this increased axial length is predominantly a consequence of increased vitreous chamber depth, rather than marked changes in any other ocular component parameter such as anterior chamber depth or lens thickness (2, 3). The prevalence of human high myopia (usually defined as eyes with Ͼ6 dioptres (D) of myopia, or Ͼ26 mm in length) is ϳ2% in the general population (1) and it is well documented that individuals with high my...

Systematic assessment of the tagging polymorphisms of the COL1A1 gene for high myopia

“…eyes (Gentle et al 2003). The study also found that posterior scleral collagen degradation was significantly increased in eyes developing myopia.…”

Post-translationally Abnormal Collagens of Prolyl 3-Hydroxylase-2 Null Mice Offer a Pathobiological Mechanism for the High Myopia Linked to Human LEPREL1 Mutations

“…It is predicted that alterations in scleral matrix properties have a function in the pathobiology of myopia (21). For example, collagen and proteoglycan expression is reduced in the sclera of a myopic animal model (45), and collagen fibril ultrastructure is altered with an increased number of smaller diameter collagen fibrils (23). This loss of matrix was shown to result from reduced collagen and proteoglycan production as well as increased collagen degradation by matrix metalloproteinases (44,45).…”

“…For example, collagen and proteoglycan expression is reduced in the sclera of a myopic animal model (45), and collagen fibril ultrastructure is altered with an increased number of smaller diameter collagen fibrils (23). This loss of matrix was shown to result from reduced collagen and proteoglycan production as well as increased collagen degradation by matrix metalloproteinases (44,45). Interestingly, only type I collagen (not type III or type V) has exhibited reduced mRNA expression levels in studies of myopic sclera (45).…”

Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia

“…22 Furthermore, reduced collagen accumulation in the sclera is observed in highly myopic eyes. 23 Importantly, another collagen prolyl hydroxylase-encoded gene, named LEPREL1, has been reported to cause autosomal-recessive high myopia with early-onset cataracts. 13,24 It is also worth noting that several clinical syndromes, such as Stickler syndrome and Marfan syndrome, in which myopia is a prominent characteristic, are caused by defects in collagen.…”