SPARC deficiency results in improved surgical survival in a novel mouse model of glaucoma filtration surgery.
Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery.
Seet
Li-Fong
LF
Ocular Wound Healing and Therapeutics Group, Singapore Eye Research Institute, Singapore, Singapore.
Su
Roseline
R
Barathi
V A
VA
Lee
Wing Sum
WS
Poh
Rebekah
R
Heng
Yee Meng
YM
Manser
Ed
E
Vithana
Eranga N
EN
Aung
Tin
T
Weaver
Matt
M
Sage
E Helene
EH
Wong
Tina T
TT
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003228:Conjunctiva / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018463:Filtering Surgery / Q000379:methods* / Q000401:mortality; D015870:Gene Expression / Q000187:drug effects; D005901:Glaucoma / Q000601:surgery*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D015676:Osteonectin / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology
D016326:Extracellular Matrix Proteins; D015676:Osteonectin; D053781:Transforming Growth Factor beta2; D003094:Collagen