Researchers have found that a crucial part of affected cells is stressed in laminitis in horses, which possibly links the disease with several human conditions.
The finding opens the possibility of new drug treatments for laminitis.
Scientists investigated whether lamellar tissue from horses with the naturally occurring, most common form of laminitis showed any evidence of endoplasmic reticulum stress.
The endoplasmic reticulum is a continuous membrane within cells comprising a network of tubules and flattened sacs. It serves several functions.
Its main role is to transport proteins and other carbohydrates to other parts of the cell and provide increased surface area for cellular reactions. They are vital to the formation of the skeleton and play a role in cell division. They also play a crucial role in the manufacture of proteins, glycogen, lipids, and other steroids such as cholesterol, progesterone and testosterone.
Researchers Lynne Cassimeris, Julie Engiles and Hannah Galantino-Homer, writing in the journal BMC Veterinary Research, says laminitis is often associated with endocrine problems that cause hyperinsulinemia – excess levels of insulin circulating in the blood relative to the level of glucose.
Indeed, recent studies have indicated that hyperinsulinemia is the driving force behind endocrinopathic laminitis.
This excessive insulin, an important stage in the development of laminitis, is expected to activate pro-growth and anabolic signaling pathways.
The study team hypothesized that chronic over-stimulation of these pathways in lamellar tissue results in stress of the endoplasmic reticulum, contributing to the tissue problems, including crucial failure of the laminae seen in the disease.
To test their hypothesis, they checked lamellar tissue from horses with naturally occurring endocrinopathic laminitis to see whether protein markers that indicate stress of the endoplasmic reticulum were present.
Three such biomarkers were found at 2.5 to 9.5 times their normal level in the lamellar tissues of 12 horses with moderate to severely laminitic front limbs when compared with half a dozen healthy control animals.
Even within the laminitic group, the markers were found be much higher in their badly affected front limbs compared to their less affected, or unaffected, hind limbs.
The presence of the three markers were described as minimal among the control horses.
The study team concluded that the endoplasmic reticulum stress pathway is active in such cases of laminitis. They found it to be most active within a subset of epidermal keratinocytes.
The findings, they said, made it sensible to explore potential links between laminitis and human diseases sharing activation of this stress pathway.
Insulin dysfunction in horses with equine metabolic syndrome resembles human metabolic syndrome and type 2 diabetes in many ways, they say, and there is a growing realization that endoplasmic reticulum stress plays a critical role in the loss of cell function in diabetes and associated diseases.
“Pharmacological options to manipulate the endoplasmic reticulum stress pathway under investigation for human disease could be applicable to laminitis treatment and prevention should this pathway prove to be a driver of disease progression,” they reported.
“Identification of shared cellular and molecular-based disease mechanisms common to equine laminitis and human diseases will leverage the extensive progress in understanding these human diseases and facilitate the identification of possible therapeutic interventions amenable to treatment of equine laminitis.”
Cassimeris is with Lehigh University in Pennsylvania; and Engiles and Galantino-Homer are with the New Bolton Center, part of the University of Pennsylvania.
Detection of endoplasmic reticulum stress and the unfolded protein response in naturally-occurring endocrinopathic equine laminitis
Lynne Cassimeris, Julie B. Engiles and Hannah Galantino-Homer
BMC Veterinary Research 2019 15:24 https://doi.org/10.1186/s12917-018-1748-x