The pathology of foot-and-mouth disease

Abstract

The equine hoof capsule protects the softer, more sensitive, structures within. Failure of the connection between hoof and bone (the lamellar, distal phalangeal attachment apparatus) results in the crippling lameness of laminitis. Dozens of different keratin molecules, with differing biomechanical properties and molecular weights, with varying degrees of hardness and sulfur concentration, are expressed in hoof tissue. Nonstop production of new hoof makes good the continual loss of hoof wall, occurring at the distal ground surface. A new calculation of the proliferative index (PI), for basal cells of the coronet and lamellae of the dorsal hoof wall, shows that active basal cell proliferation occurs only in the coronet and proximal lamellae. The remaining lamellae are virtually nonproliferative and remodeling within the hoof wall lamellae, that must occur as the hoof wall moves past the stationary distal phalanx, is a function of the controlled activation and inhibition of matrix metalloproteinases (MMPs). Proliferating coronet basal cells organize into thin, elongated cylinders (hoof wall tubules) approximately 0.2 mm in diameter. The central hollow medulla of each tubule comprises about 2% of the total hoof wall volume at the toe. The tubules of the stratum medium are arranged into zones based on the density of tubules in the intertubular horn. This tubule density gradient appears to be a mechanism for smooth energy transfer, from the rigid (high tubule density) outer wall to the more plastic (low tubule density) inner wall, and ultimately to the distal phalanx. The gradient in tubule density mirrors the gradient in water content across the hoof wall and together these factors represent an optimum design for equine hoof wall. The lamellar corium derives most of its blood supply from the branches of the terminal arch which perforates the distal phalanx. Numerous anastomoses form an arterial lattice beneath and between the epidermal lamellae and blood can flow proximally to the coronary circumflex artery and distally to the solar circumflex artery. Veins within the foot are valveless and this can be exploited clinically for retrograde venous therapy or contrast radiography (venograms). In the lamellar dermal microcirculation numerous (500/cm2) arteriovenous anastomoses connect the axial arteries to axial veins; their normal role relates to thermoregulation and pressure modulation. On the inner hoof wall (stratum internum) is the stratum lamellatum (layer of leaves) is named after the 550 to 600 epidermal lamellae (primary epidermal lamellae or PEL) which project from the surface of the inner hoof wall (stratum internum) in parallel rows. Each PEL has 150 to 200 secondary lamellae on its surface and normal SELs have a constant histological appearance that only laminitis alters. The basement membrane (BM), a tough, unbroken sheet of extracellular matrix, forms the interface between the lamellar epidermis and the dermis. It is a three-dimensional sheet of fine, anastomosing cords consisting of filaments of collagen IV ensheathed with glycoproteins, in particular laminins 1 and 5. The plasma membrane of each lamellar basal cell is attached to the BM by numerous electron dense adhesion plaques or hemidesmosomes (HDs). The various proteins of each HD occur on both sides of the basal cell plasmalemma and with anchoring filaments (AFs) form a bridge linking the interior of the basal cell to the exterior connective tissue and ultimately the distal phalanx. Importantly, HDs are maintained and assembled by glucose-consuming phosphorylation reactions and perturbations of glucose metabolism may be involved in laminitis pathogenesis. HDs and AFs are essential to normal hoof lamellar integrity and this is illustrated by horses that inherit mutations in the genes expressing these proteins. Failure to correctly express plectin or laminin5 (HD and AF proteins, respectively) results in neonatal, laminitis-like pathology. Laminitis destroys the BM and its components and without an intact, functional, basement membrane, the structure and function of the lamellar epidermis is pathologically compromised. Transcription and activation of MMP-2 occurs in normal hoof lamellae and in increased amounts during laminitis. Accidental triggering of uncontrolled, excessive MMP production of MMPs, present in the cells of the secondary epidermal lamellae, presumably for normal remodeling purposes, appears to be an important player in laminitis pathogenesis.