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Updated: Oct 10, 2025
Establishment of A Mouse Model of Aqueous Deficiency Dry Eye
Published on: November 1, 2024
Cathepsin S is a novel target for age-related dry eye
Zhiyuan Yu1, Jinmiao Li1, Gowthaman Govindarajan1
1Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States.
Abstract:
Cathepsin S (Ctss) is a protease that is proinflammatory on epithelial cells. The purpose of this study was to investigate the role of Ctss in age-related dry eye disease. Ctss-/- mice [in a C57BL/6 (B6) background] of different ages were compared to B6 mice. Ctss activity in tears and lacrimal gland (LG) lysates was measured. The corneal barrier function was investigated in naïve mice or after topical administration of Ctss eye drops 5X/day for two days. Eyes were collected, and conjunctival goblet cell density was measured in PAS-stained sections. Immunoreactivity of the tight junction proteins, ZO-1 and occludin, was investigated in primary human cultured corneal epithelial cells (HCEC) without or with Ctss, with or without a Ctss inhibitor. A significant increase in Ctss activity was observed in the tears and LG lysates in aged B6 compared to young mice. This was accompanied by higher Ctss transcripts and protein expression in LG and spleen. Compared to B6, 12 and 24-month-old Ctss-/- mice did not display age-related corneal barrier disruption and goblet cell loss. Treatment of HCEC with Ctss for 48 h disrupted occludin and ZO-1 immunoreactivity compared to control cells. This was prevented by the Ctss inhibitor LY3000328 or Ctss-heat inactivation. Topical reconstitution of Ctss in Ctss-/- mice for two days disrupted corneal barrier function. Aging on the ocular surface is accompanied by increased expression and activity of the protease Ctss. Our results suggest that cathepsin S modulation might be a novel target for age-related dry eye disease.
Insights
Cathepsin S (Ctss) increases with age and dry eye. Inhibiting Ctss may be a new treatment for age-related dry eye disease, protecting the ocular surface.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Cathepsin S (Ctss) is a proinflammatory protease.
- Age-related dry eye disease is a significant ocular surface condition.
- The role of Ctss in dry eye disease pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of Cathepsin S (Ctss) in age-related dry eye disease.
- To determine if Ctss activity and expression increase with age in the ocular surface.
- To evaluate the therapeutic potential of targeting Ctss for dry eye disease.
Main Methods:
- Compared aged and young C57BL/6 (B6) mice with and without Ctss.
- Measured Ctss activity in tears and lacrimal glands.
- Assessed corneal barrier function, goblet cell density, and tight junction protein expression (ZO-1, occludin) in vivo and in human corneal epithelial cells (HCEC).
Main Results:
- Aged B6 mice showed increased Ctss activity, transcripts, and protein expression in tears and lacrimal glands compared to young mice.
- Ctss-deficient mice (Ctss-/-) did not exhibit age-related corneal barrier disruption or goblet cell loss.
- Ctss exposure damaged corneal epithelial barrier function by disrupting occludin and ZO-1, an effect preventable by a Ctss inhibitor.
Conclusions:
- Ocular surface aging is associated with increased Cathepsin S (Ctss) expression and activity.
- Ctss contributes to age-related dry eye disease pathogenesis.
- Modulating Ctss activity presents a potential therapeutic strategy for age-related dry eye disease.
