Matrix Metalloproteinases and Structural Tissue Damage in Equine Laminitis
ACVIM 2008
J.P. Loftus1; P. Johnson2; C. Yin3; J.K. Belknap3; S.J. Black1
1University of Massachusetts, Amherst, MA, USA; 2University of Missouri, Columbia, MO, USA; 3Ohio State University, Columbus, OH, USA

Equine Laminitis affects approximately 1% of horses in the United States, causing both acute and chronic lameness. The acute case is characterized initially by pain, which is associated with inflammation but little to no derangement of the laminae. As the disease progresses to chronic laminitis, the integrity of the lamellae becomes impaired, resulting in distal displacement of the third phalanx. A prominent hypothesis for the pathogenesis of the disease is that activation of matrix metalloproteinases (MMPs) leads to destruction of the extracellular matrix components that lend structural integrity to the lamellae. The purpose of the study was to use zymography and histologic techniques to investigate the concentrations and localization of MMP-2 and MMP-9 in laminar samples from both experimental and clinical cases of laminitis. Samples from three categories of laminitis were examined: 1) laminitis induced with a gastric bolus of starch-grain gruel (CHO; Obel Grade 3, n=7), 2) clinical chronic (CHR, n=4) and 3) clinical chronic aggravated (CHR-AG, n=5) laminitis and were compared to controls (n=4). Protein extracts and thin sections of lamellar tissue were analyzed by gelatin zymography and (immuno)histochemistry, respectively. Pro-MMP-9 was elevated in most samples from the CHO, acute and CHR-AG groups. Pro-MMP-2 was elevated most consistently in the CHO and CHR-AG groups and was accompanied by increased processing to MMP-2. When zymography results were compared with H&E stained sections from the same individual, there was no overall association between elevated MMP and the extent of tissue pathology. Interestingly, in CHO-induced laminitis, MMP-2 levels were generally positively associated with tissue pathology. In contrast, in horses suffering from chronic forms of the disease MMP-2 levels appeared to have an inverse association with tissue pathology. Thin sections of laminae from 3 CHO treated horses and 3 controls were stained with an anti-equine MMP-9 mAb, which predominantly stained leukocytes (primarily neutrophils). There was no obvious association between the presence of MMP-9 positive cells and areas of overt tissue damage. These results suggest that i) MMP-2 may be involved in mechanisms of tissue repair as well as mechanisms of pathology, ii) MMP-9 is unlikely to play a direct role in gross tissue damage and iii) careful consideration of MMP inhibitors is warranted, as their therapeutic use may have deleterious effects with respect to tissue remodeling and wound healing.

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John Loftus

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