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Ocular Hypertension in Mice with a Targeted Type I Collagen Mutation

From the Hamilton Glaucoma Center, University of California San Diego, La Jolla, California.

PURPOSE. To evaluate intraocular pressure (IOP) in transgenic mice with a targeted mutation in the gene for the 1 subunit of collagen type I.

METHODS. Homozygous B6; 129-Cola1^tm1Jae mice and corresponding wild-type mice were anesthetized. A fluid-filled glass microneedle connected to a pressure transducer was then inserted through the cornea into the anterior chamber to measure IOP. All measurements were made between 11:30 AM and 1:30 PM. The IOP of seven Col1a1^r/r and eight corresponding wild-type Col1a1^+/+ male mice was measured at 12, 18, 24, and 36 weeks after birth. The IOP of 5 to 24 additional Col1a1^r/r mice was measured at 7, 12, 18, 24, and 36 weeks after birth. The structure of the anterior segment and the distribution of collagen I were assessed by immunohistochemistry.

RESULTS. Mean IOP measurements of the control Col1a1^+/+ mice (IOP_c) at 12 and 18 weeks after birth were relatively constant at 18.9 ± 2.0 and 19.2 ± 1.9 mm Hg, respectively. Mean IOP then decreased to 15.8 ± 0.8 and 16.2 ± 1.2 mm Hg at 24 and 36 weeks, respectively. In contrast, mean IOP measurements in the transgenic (Col1a1^r/r) mice was 2.7 ± 3.4 mm Hg higher at 12 weeks and increased to a maximum of 23.6 ± 2.4 mm Hg at 24 weeks. The difference between mean IOP in these two groups gradually increased to a maximum of 4.8 mm Hg (30%) at 36 weeks and was significantly different from the control mice at both 24 and 36 weeks of age. No anterior segment abnormality was observed in Col1a1^r/r mice and no difference between the anterior segment appearance of Col1a1^r/r and Col1a1^+/+ mice was observed throughout the 36-week analysis period. However, collagen I immunoreactivity in sclera and associated structures was greater in Col1a1^r/r mice than in Col1a1^+/+ mice. When the mean IOP measurements from the additional Col1a1^r/r mice were included with these measurements, mean IOP at each age was 16.7 ± 0.8, 21.8 ± 3.9, 23.2 ± 2.8, 23.5 ± 2.4, and 22.1 ± 3.6 mm Hg, respectively. Mean IOP in the Col1a1^r/r mice was significantly higher than in the Col1a1^+/+ mice at 18, 24, and 36 weeks by 21%, 44%, and 36%, respectively (P < 0.05).

CONCLUSIONS. These results demonstrate ocular hypertension in mice with a targeted type I collagen mutation and suggest there is an association between IOP regulation and fibrillar collagen turnover.

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