Laminitis in Horses: Unlocking the Mysteries

Laminitis can result from many different conditions in any breed, size and age of horse. As many as 2% of the U.S. equine  population develops laminitis each year.

Laminitis does not discriminate. It attacks without regard for breed, size, sex or age of horses. As many as 2% of the U.S. equine  population develops laminitis each year.

And perhaps most perplexing is the fact that the disease can result from many different conditions.

Bogged down by the multitude of causes that lead to the development of laminitis, Samuel Black, a veterinary professor at the University of Massachusetts, turned instead to studying the progression to end-stage laminitis – what ends up happening regardless of what kicks off the laminitic episode. Understanding that, Black came to believe, was where healing therapies would be best targeted.

Black and his research team initially began exploring the contribution of inflammation and ischemia reperfusion injury (injury that occurs when oxygen returns to tissue after a period of oxygen deficiency).

“In dissecting the biochemistry and molecular biology of the damaged laminae, I began to recognize patterns of gene and protein expression that were characteristic of end-stage disease, and these actually end up being in the laminae of laminitic horses irrespective of disease etiology,” he explained. “There are just a lot of different routes that lead to the same damaged tissue and the mechanism for that damage.

“It’s a horrendous disease,” he added, and anyone who has ever witnessed a horse suffer with the condition would agree.

While the old adage “no hoof, no horse” still applies today, researchers at the University of Massachusetts are going well beyond the hoof wall and even deeper than the cell wall to untangle the mysteries of laminitis. Thanks to research grants provided by the American Quarter Horse Foundation, the Morris Animal Foundation and USDA, Black and his team are unraveling the disease below the cellular level.

What is Laminitis? 

Laminitis’ simple definition is inflammation in the hoof. It derives its name from “lamina,” which refers to all of the parallel layers of sensitive tissue just inside the hard exterior of the hoof.

“The laminae connect the outer surface of the coffin bone to the inner hoof wall and hence suspend the horse’s axial skeleton in the hoof capsule,” Black said.

The laminae accommodate the force applied by the deep digital flexor tendon and withstand the gravitational force operating on the axial skeleton because the skeleton is hanging inside the hoof capsule supported by this tissue.

“The laminae also withstand concussive force, especially in a galloping horse where the hoof strikes the ground and the concussion waves  travel up through the hoof and pass through the laminae to the coffin bone,” he explained. “In addition, within the hoof capsule, the coffin bone remains basically steady while the hoof capsule tilts around it during motion, compressing the laminae in all directions.

“You get the impression that the digital laminae is one of the hardest-working tissues in biology.”

The digital laminae is a two-layer tissue – a dermal layer of connective tissue attached to the coffin bone and an epidermal layer of keratinized tissue connected to the inner hoof wall. These join at a layer of basal epithelial cells. When the dermalepidermal laminar junction is intact, the hoof is healthy. However, when dermal and epidermal tissue layers separate, and the complex matrix of cells that are anchoring the coffin bone begin to break down, it can be disastrous for the horse.

“You can imagine all this operating to stop the bone from rotating – flexor tendons pulling it, gravity and all the weight of this horse’s axial skeleton pushing down on it, but it’s anchored to the inner hoof wall by connective tissue – collagen fibers, the basement membrane and keratinized cells all the way out to the hoof wall,” he said. “The living layer – the most viable layer and the most dense cell layer in the whole of that thick tissue – is the layer of basal epithelial cells. If those guys fail, the tissue fails.”

When the basal epithelial cells start to be pulled away from the underlying basement membrane, the dermal laminae begin to separate from the epidermal laminae. That is when the whole tissue starts to tear, and the bone starts to rotate.

“If you can stop that early before it tears and rotates, most likely things will return to normal, and the hoof will be healthy,” he said. “If it tears and rotates really badly, most likely you will have to put your horse down.

“The science in this is to understand what’s maintaining the health of the basal epithelial layer,” he said. “How are all these different disease conditions fitting down into the basal epithelial layer to threaten its function?”

Causes of Laminitis

What researchers have found is that the basal epithelial cells, located between the epidermal and dermal layers of the digital laminae, undergo physiological change in laminitic horses, causing the tissue to fail, thus causing laminitis.

While there are many factors that initiate laminitis, the exact cause on a molecular level has not been identified. So, graduate student Erica Pawlak initially began looking at the roles of certain enzymes – matrix metalloproteinases (MMPs) 1, 2, 9 and 13, and aggrecanase 1 (ADAMTS-4) – in laminitis. Sam and the research team have ruled out MMP 9 as having a role in laminitis, and suggest that MMP-2 plays only a minor role.

Based on their research, they now know that the MMP 1, MMP 13 and ADAMTS-4 enzymes are in the cells at the junction of the epidermal and dermal digital laminae and that ADAMTS-4 and MMP-13 are present as active forms and elevated in laminitic laminae. They suspect that high concentrations of these enzymes are what cause the tissue to fail.

“Two things can change the way the basal epithelial cells maintain the epidermal-dermal junction,” Black explained. “One thing would be if you got a lot of enzymes produced that chew up the attachment proteins that tether the cells to underlying basement membrane. Another would be if you get physiologic changes in the cells that shut down genes that encode the proteins that make the attachment proteins. “In reality, both things are happening in severe conditions. The MMPs are likely involved in disassembly of the attachment structures, while signaling pathways control expression of the attachment proteins. We want to address these processes therapeutically.”

If the cause of the tissue breakdown is discovered, researchers will be a step closer to creating a therapy to stop laminitis from progressing to a life-threatening event.

“Under normal conditions, the hoof works darn well by compensating all imposed forces, and if you change the imposed forces like in supporting limb laminitis, things start to go wrong,” Black said. “If you change the behavior of the cells within the structure as a result of metabolic changes in the animal or another physiologic event, it all goes haywire. And ‘haywire’ turns out to have a characteristic molecular pattern in terms of end-stage disease.”

By Jennifer K. Hancock
Courtesy of American Quarter Horse Association