title: Reduced Scleral TIMP-2 Expression Is Associated With Myopia Development: TIMP-2 Supplementation Stabilizes Scleral Biomarkers of Myopia and Limits Myopia Development.
abstract: The purpose of this study was to determine the endogenous regulation pattern of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the tree shrew sclera during myopia development and investigate the capacity of exogenous TIMP-2 to inhibit matrix metalloproteinase-2 (MMP-2) in vitro and both scleral collagen degradation and myopia development in vivo.
  
  
  
  TIMP-2 expression in the sclera during myopia development was assessed using polymerase chain reaction. In vitro TIMP-2 inhibition of MMP-2 was investigated using a gelatinase activity plate assay and zymography. Tree shrews were injected with a collagen precursor before undergoing monocular form deprivation and concurrent daily subconjunctival injections of either TIMP-2 or vehicle to the form-deprived eye. In vivo ocular biometry changes were monitored, and scleral tissue was collected after 12 days and assayed for collagen degradation.
  
  
  
  The development of myopia was associated with a mean reduction in TIMP-2 mRNA expression after 5 days of form deprivation (P < 0.01). Both activation and activity of MMP-2 were inhibited by TIMP-2 with an IC50 of 10 to 20 and 2 nM, respectively. In vivo exogenous addition of TIMP-2 significantly reduced myopia development (P < 0.01), due to reduced vitreous chamber elongation (P < 0.01). In vivo TIMP-2 treatment also significantly inhibited posterior scleral collagen degradation relative to vehicle-treated eyes (P < 0.01), with levels similar to those in control eyes.
  
  
  
  Myopia development in mammals is associated with reduced expression of TIMP-2, which contributes to increased degradative activity in the sclera. It follows that replenishment of this TIMP-2 significantly reduced the rate of both scleral collagen degradation and myopia development.
authors.affiliation: Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia 2School of Optometry and Vision Science, University of California Berkley, Berkley, California, United States.
authors.forename: Hsin-Hua
authors.initials: HH
authors.lastname: Liu
authors.affiliation: Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Kenning
authors.affiliation: Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia 3Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Jobling
authors.affiliation: Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Neville A
authors.initials: NA
authors.lastname: McBrien
authors.affiliation: Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia 4School of Medicine, Deakin University, Geelong, Victoria, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Gentle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001699:Biometry; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use; D009216:Myopia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D012333:RNA, Messenger; D060888:Real-Time Polymerase Chain Reaction; D012590:Sclera / Q000201:enzymology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use*; D014417:Tupaia
chemical_list: D015415:Biomarkers; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D012313:RNA; D003094:Collagen