Leukocyte-derived and endogenous matrix metalloproteinases in the lamellae of horses with naturally acquired and experimentally induced laminitis.
Authors: Loftus, Johnson, Belknap, Pettigrew, Black
Journal: Veterinary immunology and immunopathology
Summary
# Editorial Summary: Matrix Metalloproteinases in Equine Laminitis Dysregulation of matrix metalloproteinases (MMPs) drives lamellar tissue breakdown in laminitis, yet the relative contributions of inflammatory cell infiltration versus endogenous MMP production remain poorly understood. Loftus and colleagues examined archived lamellar tissue from horses with naturally acquired laminitis, starch-induced responders (which developed severe lameness) and non-responders, plus healthy controls, using gelatin zymography to quantify gelatinase activity, myeloperoxidase ELISA to assess leukocyte burden, and real-time PCR to measure expression of MMP-processing enzymes. ProMMP-9 levels correlated directly with lamellar neutrophil and monocyte infiltration, indicating leukocyte-derived production, whereas proMMP-2 and MMP-2 elevation occurred independently of inflammatory cell numbers—suggesting distinct upstream triggers for these two gelatinases. Neither MT1-MMP nor PACE4 expression was upregulated despite elevated MMP-2, indicating the processing mechanism remains unclear and likely involves post-translational regulation. These findings fundamentally reshape our understanding of laminitis pathogenesis as a condition with separable inflammatory and endogenous enzymatic components, with substantial individual variation in MMP profiles even among horses presenting with identical clinical grades—a distinction that may ultimately refine prognostic assessment and guide targeted therapeutic interventions aimed at specific enzymatic pathways rather than inflammation broadly.
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Practical Takeaways
- •Inflammatory cell infiltration (neutrophils/monocytes) and endogenous enzyme dysregulation may require different therapeutic targets, not a single anti-inflammatory approach
- •Variability in MMP profiles among laminitic horses could inform prognosis and treatment planning, potentially distinguishing different disease subtypes
- •Understanding that MMP dysregulation occurs independently of inflammation suggests some cases may benefit from enzyme-modulating therapies even when systemic inflammation is controlled
Key Findings
- •ProMMP-9 levels were significantly elevated in horses with acute/aggravated laminitis and correlated directly with myeloperoxidase content, indicating leukocyte-derived production
- •ProMMP-2 and MMP-2 were increased in some laminitis groups but showed no correlation with myeloperoxidase or proMMP-9, suggesting independent endogenous regulation
- •Leukocyte infiltration and dysregulation of endogenous MMP-2 appear to be independent processes with distinct inducers in laminitis pathogenesis
- •MT1-MMP and PACE4 gene expression were not elevated in any disease group despite increased MMP-2, suggesting alternative proMMP-2 processing mechanisms in laminitis