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Metalloproteinases and Pathological Tissue Remodeling in Equine Laminitis

Principal Investigator/Project Leader: 
Department of Project: 
Veterinary & Animal Sciences Dept.
Project Description: 

Laminitis is a crippling disease that affects about one-percent of the more than nine million horses in North America. The cost of laminitis to the horse industry exceeds $1 billion annually, predominantly from loss of use of the affected animals rather than medical costs. Laminitis results from failure of the digital laminae, which suspend a horse's distal phalanx, and thus the axial skeleton and all that is attached to it, within the hoof capsule. The laminae are composed of a hoof wall-associated epidermal layer and a distal phalanx-associated dermal layer. These complex interdigitated structures join at a basement membrane (BM) which is synthesized by specialized cells (called basal epithelial cells) located at the boundary of the digital epidermis. In laminitis, the epidermal and dermal layers separate within regions of the laminae, causing the distal phalanx to rotate under torque applied by the digital flexor tendon and to sink under the weight of the axial skeleton. The extent to which rotation and sinking occurs depends on how much of the laminae is compromised by separation of epidermal and dermal laminae.

Failure of the laminae in laminitis is thought to result from degradation of lamellar basement membrane and neighboring extracellular matrix (ECM), possibly reflecting changes in the physiology of epithelial cells that maintain the BM, or from processes initiated by immigrant inflammatory leukocytes, or both. While details of the processes that disassemble the laminar ECM in laminitis are not known, consensus opinion favors the involvement or one or more metalloproteinases (MPs). Our goals are to identify the MPs expressed in healthy and laminitic laminae and to determine their contributions to normal lamellar function and degradation of the tissue in laminitis. It is anticipated that identification of the specific metalloproteinases responsible for pathologic remodeling of the laminar ECM in laminitis will ultimately lead to the identification of inhibitors that can be delivered to inflamed laminae to protect horses at risk of laminitis and to treat animals that show signs of lameness but have not yet progressed to catastrophic failure of the laminae. These goals are endorsed by the Morris Animal Foundation, the American Association of Equine Practitioners, the Grayson-Jockey Club Foundation and the USDA.