Research supports the theory that collagen may play an important role in connective tissue-related disorders in Friesian horses.
THE ROLE OF COLLAGEN
The term collagen comes from the Greek word kola (meaning “glue”). The word originated from the use of animal skin and collagen-rich tissues to make glue. In a broader sense, collagen is, in fact, the “glue” of all mammalian bodies, including horses and humans. Collagen essentially holds the body together by providing elasticity and strength to most tissues wherever mechanical function is essential, such as skin, cartilage, tendons, and bones. The collagen superfamily comprises 28 variations of collagen, which are differentiated by Roman numerals (Collagen I, Collagen II, etc.).
The collagen family of proteins is the most abundant in the body – representing the basic building blocks of nearly every tissue and organ. Collagen structures form largely by cell-mediated self-assembly of small collagen molecules. During the process of collagen self-assembly, various types of inter-molecular “cross-links” stabilize the molecular structures as they form. Whether in the early stages of embryonic tendon development or the late stages of connective tissue disease, collagen cross-links play a crucial role in tissue mechanics, cell signaling, tissue damage, and repair.
The main functional feature of most collagen is mechanical load bearing of tensile strength, which results from the highly sophisticated architectural arrangement of collagen substructures and other proteins such as elastin and water-binding proteoglycans. Although soft connective tissues are composed of nearly identical basic molecular building blocks, their varied arrangement allows for an exquisite range of potential tissue mechanical properties. The cells that mediate the functional assembly of collagen do so according to their gene expression and the mechanical demands on the tissue.
Within any collagenous connective tissue, the functional building blocks that provide tensile strength and elasticity are called collagen fibrils. Research suggests that mature collagen fibrils are highly elastic structures – meaning that they mechanically load and unload in a mostly reversible fashion. The defining functional requirement of these protein superstructures is to be able to reversibly load and unload without damage. Thus, collagen cross-links are a central enabler (and potential disabler) of connective tissue function.
CONNECTIVE TISSUE-RELATED DISORDERS IN FRIESIANS
Much work has been done in recent years to unlock the answers to several diseases affecting Friesian horses in which the role of collagen is suspected to play a part. While more research is needed, the below unusual findings in Friesian horses support the theory that a general collagen-based syndrome might be responsible for several, if not all, connective tissue-related disorders in Friesian horses.
In both hydrocephalus and dwarfism, a mutation in a gene involved in protein glycosylation was detected. Without proper protein glycosylation, collagen molecules do not form the structural fibrils needed to provide collagen’s tensile strength and elasticity. Interestingly, Friesian foals with dwarfism are also affected by tendon laxity. A genetic test is now available for hydrocephalus and dwarfism in Friesians.
Relatively high cross-link concentrations and lower collagen concentrations in both the superficial digital flexor tendons and common digital extensor tendons in Friesians suggests an inferior collagenous extracellular matrix content. Additionally, research has demonstrated deep flexor tendon tissue from Friesian horses contains less collagen cross- links compared to Warmblood horses.
Postmortem examination of the aortic wall of Friesians diagnosed with aortic rupture revealed significant disorganization of collagen fibers. The findings suggest a connective tissue-related disorder affecting elastin or collagen in the aortic media is the potential underlying cause of aortic rupture in Friesian horses. It is noteworthy that in humans with aortic disease, there are several known related connective tissue abnormalities, one of them being increased collagen cross-linking. It is conceivable that an underlying genetic defect of the connective tissue in the aortic media predisposes Friesian horses to aortic rupture, dissection, and aortopulmonary fistulation at a specific location. The Friesian horse is also the only known animal species in which aortopulmonary fistulation is regularly encountered.
In Friesians with megaesophagus, an increased amount of irregular collagen was found, primarily in the non-dilated parts of the esophagus. Significantly more collagen was deposited between large muscle fibers and collagen fibers in the esophagus of affected horses. Additionally, collagen was disorganized, less condensed, and presented as small, clumped structures. The increased occurrence of megaesophagus in Friesians compared to other horse breeds, together with the presence of irregular collagen in very young foals, supports the hypothesis that megaesophagus is a hereditary trait in Friesian horses. Genetic research is currently underway to identify the gene variant responsible for megaesophagus in Friesians.
Friesians have a suspected predisposition to the development of primary gastric rupture, which is theorized to potentially be a result of an underlying connective tissue-related disorder.
COLLAGEN-SPECIFIC RESEARCH IN FRIESIANS
In 2018, Ghent University in Belgium released the results of a study that attempted to delve further into the relationship between collagen and several genetic diseases in Friesians. Their goal was to examine the collagen catabolism rate of Friesians compared to other breeds. Catabolism is the process in which larger structures like proteins, fats, or tissues are broken down into smaller units such as cells or fatty acids. During tissue catabolism, collagen cross-links are released into the body’s circulatory system and later excreted in the urine. In human medicine, the excretion of collagen cross-links in urine can be monitored to diagnose diseases.
Researchers at Ghent University theorized they could demonstrate a breed-related difference in collagen catabolism by examining the rate of collagen degradation byproducts as compared to Warmblood horses. During the study, urine samples were obtained from 17 Friesians and 17 Warmbloods. Tests were performed to compare the levels of two specific types of collagen cross-links:
Pyridinoline (PYD) is widespread throughout the body and is found in the collagen of several connective tissues, including cartilage, blood vessels, fascia, muscles, and ligaments.
Deoxypyridinoline (DPD) is mainly present in collagen found in bones and teeth.
The results revealed a significantly higher than average ratio of PYD/DPD in the urine of Friesian horses compared to that of Warmbloods. Additionally, urinary PYD was significantly higher in Friesians than in Warmbloods. Interestingly, elevated PYD/DPD ratios have been observed in human patients with scleroderma, a disease characterized by systemic excessive collagen deposition that is attributed to increased collagen catabolism.
While the exact origin of excreted collagen cross-links cannot be determined, it is likely the cross-links originate from soft connective tissue catabolism. This difference in collagen catabolism could explain the predisposition of Friesians to connective tissue-related disorders.
References: Saey, Veronique & Tang, Jonathan & Ducatelle, Richard & Croubels, Siska & Baere, Siegrid & Schauvliege, Stijn & van Loon, Gunther & Chiers, Koen. Elevated urinary excretion of free pyridinoline in Friesian horses suggests a breed-specific increase in collagen degradation. BMC Veterinary Research. (2018).
Leegwater PA, Vos-Loohuis M, Ducro BJ, Boegheim IJ, van Steenbeek FG, Nijman IJ, Monroe GR, Bastiaansen JWM, Dibbits BW, van de Goor LH, Hellinga I, Back W, Schurink A. Dwarfism with joint laxity in Friesian horses is associated with a splice mutation in B4GALT7. BMC Genomics. (2016).
Ducro BJ, Schurink A, Bastiaansen JW, Boegheim IJ, van Steenbeek FG, Vos-Loohuis M, Nijman IJ, Monroe GR, Hellinga I, Dibbits BW, Back W, Leegwater PA. A nonsense mutation in B3GALNT2 is concordant with
hydrocephalus in Friesian horses. BMC Genomics. (2015).
Ploeg, Margreet. Challenging Friesian horse diseases: aortic rupture and megaesophagus. (2015).
Winfield LS, Dechant JE. Primary gastric rupture in 47 horses. (2013).
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