Biomechanical Properties and Correlation With Collagen Solubility Profile in the Posterior Sclera of Canine Eyes With anADAMTS10Mutation

Abstract

Citation: Palko JR, Iwabe S, Pan X, Agarwal G, Komáromy AM, Liu J. Biomechanical properties and correlation with collagen solubility profile in the posterior sclera of canine eyes with an ADAMTS10 mutation. Invest Ophthalmol Vis Sci. 2013;54:268554: -269554: . DOI:10.1167 PURPOSE. We examined the biomechanical properties and correlation with the collagen solubility profile of the posterior sclera in a canine model of primary open-angle glaucoma caused by the G661R missense mutation in the ADAMTS10 gene. METHODS.Scleral strips from ADAMTS10-mutant (affected) dogs and age-matched controls were collected. Viscoelastic properties (i.e., complex modulus and tan[d]) were measured using dynamic mechanical analysis (DMA) with a 0.15% sinusoidal strain at different frequencies superimposed upon different preloads. A tensile ramp was performed following DMA. The collagen solubility profile was examined using a colorimetric hydroxyproline assay to determine the amount of soluble and insoluble collagen. The viscoelastic properties were compared between groups using linear mixed models for repeated measures at different preloads and frequencies. The correlation between the biomechanical properties and collagen content were evaluated using Pearson correlations. RESULTS.Complex modulus and tan(d) were significantly lower in the affected group (P < 0.001), and the differences were consistent at different preloads and frequencies. The B value from the tensile ramp test also was significantly lower in the affected group (P ¼ 0.02). The insoluble collagen was significantly lower in the affected group (P < 0.05) and correlated positively with the complex modulus (R ¼ 0.88, P < 0.005).CONCLUSIONS. An inherently weaker and biochemically distinct posterior sclera was observed in dogs with the G661R missense mutation in ADAMTS10 before clinical indications of optic nerve damage. It remains to be shown whether and how the altered scleral biomechanics may affect the rate of glaucoma progression following intraocular pressure elevation.

Changes of the Expressions of Orphan and gon- ADAMTS in Chondrosarcoma Cells

“…Like other ADAMTS, ADAMTS10 mutations may change biomechanical features of ECM in animals. 34 In our study, after insulin application, ADAMTS10 levels decreased in OUMS-27. Gruber et al 35 showed that ADAMTS10 was decreased in intervertebral disk degeneration.…”

A Novel Missense Mutation in ADAMTS10 in Norwegian Elkhound Primary Glaucoma

“…It may have a role in the storage and activation of latent transforming growth factor beta (TGF β ), which regulates the collagen turnover [41]–[43] as well as in the remodeling of the mesenchymal and basement membranes [44].…”

“…It maintains the lens in its position via lens ligaments, which are comprised primarily from fibrillin-1 [43]. Microfibrils localize and activate TGF β [45].…”

Genetics of Canine Primary Glaucomas

“…[65][66][67][68] Abnormalities in the ECM and the biomechanics of the optic nerve head's lamina cribrosa and the sclera also contribute to greater susceptibility of retinal ganglion cells to variations in IOP. [69][70][71][72][73][74][75] The recent discoveries of ADAMTS10 mutations responsible for POAG in beagles and Norwegian elkhounds, 25,76 as well as a mutation in ADAMTS17 causing canine PLL in many breeds, 29,77 and ongoing studies of canine POAG by the authors and others, 8,10 revealed that many forms of primary canine glaucoma are closely related to a group of connective tissue disorders resulting from abnormal microfibril formation. These so-called microfibrillopathies include Weill-Marchesani syndrome (WMS) and Marfan syndrome (MS) and are caused by mutations in genes responsible for normal microfibril formation, most importantly ADAMTS10, ADAMTS17, and fibrillin-1 (FBN1), resulting in defective microfibrils.…”

“…78,80,85,94,95 In support of the proposition that an abnormal ECM metabolism results from mutations in ADAMTS10, the authors observed that the sclera of mutant beagles is weaker and has biochemical differences compared with wild-type tissue. 75 They posit that the altered biomechanical properties of the ADAMTS10-mutant sclera has a neuroprotective effect and may partially explain their clinical observation that POAG-affected beagles maintain vision longer at high IOPs than PACG-affected dogs without an ADAMTS10 mutation.…”