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Rac1 Inhibition Prevents Tissue Contraction and MMP Mediated Matrix Remodeling in the Conjunctiva

Tovell, VE; Chau, CY; Khaw, PT; Bailly, M; (2012) Rac1 Inhibition Prevents Tissue Contraction and MMP Mediated Matrix Remodeling in the Conjunctiva. Investigative Ophthalmology & Visual Science , 53 (8) pp. 4682-4691. 10.1167/iovs.11-8577. Green open access

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Abstract

PURPOSE: To evaluate the efficiency of Rac1 inhibition in preventing matrix contraction by Tenon's capsule fibroblasts. METHODS: The involvement of Rac1 in serum-stimulated matrix contraction by human Tenon's fibroblasts (HTFs) was investigated in a classic collagen contraction model and our ex vivo model of tissue contraction using immunocytochemistry, chemical inhibitors, and small interfering RNA (siRNA) technology. Matrix integrity was assessed using confocal reflection microscopy and Coomassie blue staining. Quantitative real-time polymerase chain reaction (QRT-PCR) and Western blot analysis were used to assess matrix metalloproteinase (MMP) expression. RESULTS: Serum induced Rac1 activation in HTF-populated collagen gels and stimulated HTFs to contract collagen matrices down to ∼90% of their original size. Rac1 inhibition using NSC23766 or depletion using siRNA both significantly reduced HTF-mediated contraction. Early brief exposure to NSC23766 reduced HTF-mediated gel contraction by 70%, while transient treatment with the Rac1 inhibitor once a week decreased ex vivo tissue contraction down to serum-free levels. Transient exposure to NSC23766 prevented early cell protrusions, fiber alignment, and matrix degradation, as seen upon continuous exposure to broad-spectrum MMP inhibitor. However, unlike MMP inhibition, transient treatment with NSC23766 led to a significant reduction in MMP1 mRNA and protein expression during contraction, without increasing MMP2 and MMP14 expression. CONCLUSIONS: Rac1 inhibition efficiently prevents conjunctival tissue and collagen matrix contraction and prevents matrix degradation.

Type: Article
Title: Rac1 Inhibition Prevents Tissue Contraction and MMP Mediated Matrix Remodeling in the Conjunctiva
Open access status: An open access version is available from UCL Discovery
DOI: 10.1167/iovs.11-8577
Publisher version: http://dx.doi.org/10.1167/iovs.11-8577
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: OPHTHALMOLOGY, GLAUCOMA FILTRATION SURGERY, RHO-GTPASES, WOUND CONTRACTION, IN-VIVO, EXPRESSION, FIBROBLASTS, METALLOPROTEINASES, REPAIR, HOMEOSTASIS, BEHAVIOR
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1349511
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