Leukocyte-derived and endogenous matrix metalloproteinases in the lamellae of horses with naturally acquired and experimentally induced laminitis.
Abstract: Inflammation and dysregulation of endogenous matrix metalloproteinase (MMP) production are implicated in the development of equine laminitis. In this study, we examine quantitative relationships among levels of leukocyte-derived proMMP-9 and MMP-9, lamellar proMMP-2 and MMP-2, and expression of proMMP-2 processing enzymes, MT1-MMP/PACE4, as steps towards determining whether inflammation and dysregulation of endogenous MMP production are independent or co-dependent processes. Methods: Archived samples of lamellae from horses with naturally acquired laminitis (n = 12), and from horses administered a pro-laminitic gastric bolus of starch gruel were used, the latter horses falling into two groups: (i) responders (CHO-R, n = 7), which developed Obel grade 3-lameness and (ii) non-responders (CHO-NR, n = 4), which did not become lame. Methods: Lamellar tissue extracts were analyzed by gelatin zymography to determine gelatinase content and by a myeloperoxidase ELISA to quantify relative monocyte/neutrophil content in the tissue. Real-time PCR was employed to measure gene expression of MT1-MMP and PACE4. Conclusions: Extracts of lamellae from control horses, CHO-NR and horses with chronic (non-aggravated) laminitis had similarly low levels of pro and processed MMP-9 and MMP-2. In contrast, proMMP-9 was significantly elevated in extracts of lamellae from CHO-R and horses with naturally acquired acute and aggravated chronic laminitis. Lamellar MMP-2 was also increased significantly in the CHO-R and aggravated chronic laminitis groups, although not in the horses with naturally acquired acute laminitis. Concentrations of proMMP-9 correlated directly with myeloperoxidase content in lamellar extracts, suggesting production/induction by inflammatory leukocytes. In contrast, concentrations of proMMP-2 and MMP-2 were unrelated to concentrations of myeloperoxidase or proMMP-9 suggesting that leukocyte infiltration and dysregulation of endogenous MMP-2 are independent processes most likely with distinct inducers. Neither MT1-MMP nor PACE4 gene expression was elevated relative to controls in any group; this is discussed with respect to proMMP-2 processing in disease. In addition, variability in relative concentrations of lamellar MMPs observed among horses with Obel grade 3-lameness is discussed in the context of laminitis risk assessment and disease outcome.
Publication Date: 2008-11-07 PubMed ID: 19101039DOI: 10.1016/j.vetimm.2008.11.003Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- Non-P.H.S.
Summary
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This study explores the roles of inflammation, white blood cells, and a group of enzymes called matrix metalloproteinases (MMP) in the development of laminitis, a painful crippling condition affecting horses’ feet. It suggests that inflammation and an imbalance of MMP enzyme production could be separate contributing processes to the disease.
Study Methodology
- The research used archived samples of lamellar tissue from horses that had naturally developed laminitis and horses that were given a starch gruel mixture which increases the risk of laminitis.
- Horses given the gruel were divided into two groups: responders who developed lameness (a sign of laminitis) and non-responders who stayed sound.
- The researchers used various testing methods including gelatin zymography, myeloperoxidase ELISA, and real-time PCR to measure different markers, enzymatic activities and gene expression in the tissue extracts.
Results and Interpretation
- The study found that levels of MMP-9, an enzyme that helps break down certain proteins within cells, were significantly higher in lamellar extracts from horses who developed lameness after being fed the starch gruel and in horses with naturally developed acute and chronic laminitis.
- Lamellar MMP-2, another similar enzyme, also saw significant increases in the same categories though not in the case of naturally developed acute laminitis.
- There was a connection noted between high levels of proMMP-9 and myeloperoxidase in lamellar extracts, suggesting that inflammation and white blood cell activity could be inducing these increased levels.
- Levels of proMMP-2 and MMP-2 didn’t seem to be linked to inflammation or white blood cell activity, indicating they may be influenced by different factors. Therefore, inflammation and imbalanced MMP production could be considered independent contributors to laminitis.
- No noticeable increases in gene expression of either MT1-MMP or PACE4 were found in any groups. Since these substances contribute to the processing of proMMP-2, their possible role in disease progression is discussed further.
- Differences in MMP concentrations among different horses exhibiting the same level of lameness were noted as potentially significant for laminitis risk assessment and predicting disease outcomes.
Cite This Article
APA
Loftus JP, Johnson PJ, Belknap JK, Pettigrew A, Black SJ.
(2008).
Leukocyte-derived and endogenous matrix metalloproteinases in the lamellae of horses with naturally acquired and experimentally induced laminitis.
Vet Immunol Immunopathol, 129(3-4), 221-230.
https://doi.org/10.1016/j.vetimm.2008.11.003 Publication
Researcher Affiliations
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
MeSH Terms
- Animals
- Carbohydrates / toxicity
- Female
- Foot Diseases / chemically induced
- Foot Diseases / enzymology
- Foot Diseases / veterinary
- Gene Expression Regulation, Enzymologic / drug effects
- Gene Expression Regulation, Enzymologic / physiology
- Hoof and Claw / enzymology
- Hoof and Claw / pathology
- Horse Diseases / chemically induced
- Horse Diseases / metabolism
- Horses
- Inflammation / chemically induced
- Inflammation / enzymology
- Inflammation / veterinary
- Leukocytes / enzymology
- Male
- Matrix Metalloproteinases / genetics
- Matrix Metalloproteinases / metabolism
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