Targeting the cochlin/SFRP1/CaMKII axis in the ocular posterior pole prevents the progression of nonpathologic myopia

Communications Biology · 10 authors, 3 centres

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TL;DR

This preclinical study using guinea pig myopia models identifies a novel signaling axis (cochlin/SFRP1/CaMKII) between retinal, RPE, and choroidal cells. Genetic knockdown of cochlin or pharmacological blockade of SFRP1 prevented myopia progression by improving choroidal circulation.

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The study employed guinea pig form-deprived and lens-induced myopia models, along with human RPE cells and a simian choroidal endothelial cell line. Proteomic analysis of ocular posterior pole tissues identified upregulation of cochlin protein at the retina-RPE interface. Microarray analysis showed cochlin upregulated SFRP1 expression in RPE cells. In choroidal endothelial cells, SFRP1 elevated intracellular Ca2+ and activated CaMKII signaling, causing endothelial dysfunction. Genetic knockdown of cochlin and pharmacological blockade of SFRP1 abrogated reduced choroidal blood perfusion and prevented myopia progression in the form-deprived model. The findings suggest this novel axis contributes to nonpathologic myopia pathogenesis and represents potential interventional targets. Limitations include the lack of validation in clinical samples and the possibility that protein overexpression could be a consequence rather than a cause of eye elongation.

STUDY TYPE

other

SPECIALTY

ophthalmology

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AI pipeline

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ORIGINAL PAPER

PMC10465513

Targeting the cochlin/SFRP1/CaMKII axis in the ocular posterior pole prevents the progression of nonpathologic myopia

Communications Biology

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ABSTRACT

Myopia is a major public health issue. However, interventional modalities for nonpathologic myopia are limited due to its complicated pathogenesis and the lack of precise targets. Here, we show that in guinea pig form-deprived myopia (FDM) and lens-induced myopia (LIM) models, the early initiation, phenotypic correlation, and stable maintenance of cochlin protein upregulation at the interface between retinal photoreceptors and retinal pigment epithelium (RPE) is identified by a proteomic analysis of ocular posterior pole tissues. Then, a microarray analysis reveals that cochlin upregulates the expression of the secreted frizzled-related protein 1 (SFRP1) gene in human RPE cells. Moreover, SFRP-1 elevates the intracellular Ca 2+ concentration and activates Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) signaling in a simian choroidal vascular endothelial cell line, and elicits vascular endothelial cell dysfunction. Furthermore, genetic knockdown of the cochlin gene and pharmacological blockade of SFRP1 abrogates the reduced choroidal blood perfusion and prevents myopia progression in the FDM model. Collectively, this study identifies a novel signaling axis that may involve cochlin in the retina, SFRP1 in the RPE, and CaMKII in choroidal vascular endothelial cells and contribute to the pathogenesis of nonpathologic myopia, implicating the potential of cochlin and SFRP1 as myopia interventional targets.

CITATION EXPORT

Chao Geng, Siyi Liu, Jindan Wang et al.. Targeting the cochlin/SFRP1/CaMKII axis in the ocular posterior pole prevents the progression of nonpathologic myopia. Communications Biology. (2023). https://doi.org/10.1038/s42003-023-05267-2

AUTHORS

10 · 3 CENTRES

Chao Geng, Siyi Liu, Jindan Wang, Sennan Wang, Weiran Zhang, Hua Rong, Yunshan Cao, Shuqing Wang, Zhiqing Li, Yan Zhang

1https://ror.org/04j2cfe69grid.412729.b0000 0004 1798 646XTianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 300384 Tianjin, China
2grid.32566.340000 0000 8571 0482Department of Cardiology, Gansu Provincial Hospital, Lanzhou University, 730000 Lanzhou, Gansu Province China
3https://ror.org/02mh8wx89grid.265021.20000 0000 9792 1228School of Pharmacy, Tianjin Medical University, 300070 Tianjin, China