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Laminitis Research and Education

Laminitis Research and Education Equine laminitis research and education The Laminitis Laboratory at New Bolton Center was founded in 2008. Laminitis is a common and debilitating disease that affects the epidermal and dermal lamellae.

The lamellae normally allow the transfer of the horse's weight from the skeletal elements of the digit to the hoof wall. The Laminitis Laboratory was formed in part due to the tragic loss of the 2006 Kentucky Derby winner, Barbaro, to laminitis in January, 2007. Our goal is to better understand laminitis pathogenesis in order to improve the prevention, diagnosis, and treatment of this disease. Our

The lamellae normally allow the transfer of the horse's weight from the skeletal elements of the digit to the hoof wall. The Laminitis Laboratory was formed in part due to the tragic loss of the 2006 Kentucky Derby winner, Barbaro, to laminitis in January, 2007. Our goal is to better understand laminitis pathogenesis in order to improve the prevention, diagnosis, and treatment of this disease. Our

Operating as usual

New Paper! Open Access!https://doi.org/10.1371/journal.pone.0277284What “Witch Nails” in mice tells us about equine hoof...
11/14/2022

New Paper! Open Access!
https://doi.org/10.1371/journal.pone.0277284

What “Witch Nails” in mice tells us about equine hoof biology and laminitis

For many years, the gold standard for determining the biological function of a protein has been to see how mutation or removal of the protein through artificial genetic engineering or natural mutation impacts the structure, physiology, or behavior (“phenotype”) of the organism carrying the genetic mutation. This mode of investigation is not practical for studies of equine laminitis and hoof biology, for obvious reasons, and to date, there have been few published studies on nail unit biology (claw and associated anatomical structures) in the laboratory animal model of choice, the mouse.

John Sundberg of The Jackson Laboratory of Bar Harbor, Maine, Robert Rice of UC Davis, Hannah Galantino-Homer of the University of Pennsylvania School of Veterinary Medicine (Penn Vet) and co-authors have reported in PLOS One on a genetic mutation of a keratin gene in mice that provides insight into the biology and development of the claw of the mouse and equine hoof (Sundberg, 2022). The mutated protein is a keratin, KRT90, and is expressed in the nail bed of the claw, which is, like the hoof lamellae, the tissue under the claw that connects the claw to the distal phalangeal bone of the digit. The genetic mutation does not eliminate KRT90, but it does change the structure of part of the protein that is important in formation of structures that comprise the “skeleton” of keratinocytes. Like a skeleton, the cell skeleton, or cytoskeleton, is essential for the ability of cells and the tissues they form to resist mechanical forces and maintain structural integrity. Mice with the KRT90 mutation develop what the authors have named the “witch nail” phenotype. The claws of these mice are long and curved, the nail bed is thickened, and the connection between the nail bed and underlying digit is more readily broken, resulting in sloughing of claws in some cases.

The Galantino-Homer lab had previously produced and characterized monoclonal antibodies to equine KRT124, which is the equine equivalent of KRT90 of mice (Armstrong et al., 2019). Those studies had shown that KRT124 is tightly restricted to the hoof lamellae where it pairs with KRT42 to form the most abundant cytoskeletal proteins of the hoof lamellae (Carter et al., 2010), suggesting that KRT124 might have a specialized role in the mechanical suspension of the horse’s distal phalangeal bone (or “coffin bone”) within the hoof capsule. This suspensory apparatus of the distal phalanx is an essential feature of equine anatomy as well as the structure that fails in horses with laminitis. John Sundberg contacted Hannah Galantino-Homer at Penn Vet in early 2020 about the potential relevance of the witch nails mutation to equine laminitis. They noted that there are interesting parallels between the pathology of the nail bed/lamellae in the mouse mutant and in horses with chronic laminitis. The current study used the antibodies against equine KRT124 to demonstrate that KRT90 localizes to the nail bed in wild type mice. This localization and the pathology observed in the witch nail mutants support the idea that KRT90/KRT124 is critical for the form and function of the nail unit.
Interestingly, humans, who do not bear weight on their nails, have lost the ability to express the KRT90 gene and therefore do not have this keratin. The mouse mutation is still useful as a model of nail disease since it allows investigators to examine the downstream impact of nail bed fragility and damage on nail growth, mechanical integrity, inflammatory processes, and secondary effects on the adjacent distal phalangeal bone.

Armstrong, C., Cassimeris, L., Santos, C. D. S., Micoogullari, Y., Wagner, B., Babasyan, S., Brooks, S., & Galantino-Homer, H. (2019). The expression of equine keratins K42 and K124 is restricted to the hoof epidermal lamellae of Equus caballus. PLoS One, 14(9), e0219234. https://doi.org/https://doi.org/10.1371/journal.pone.0219234

Carter, R. A., Shekk, V., de Laat, M. A., Pollitt, C. C., & Galantino-Homer, H. L. (2010). Novel keratins identified by quantitative proteomic analysis as the major cytoskeletal proteins of equine (Equus caballus) hoof lamellar tissue. J Anim Sci, 88(12), 3843-3855.

Sundberg, J. P. Galantino-Homer, H.; Fairfield, H.; Ward-Bailey, P.F.; Harris, B.S.; Berry, M.; Pratt, C.H.; Gott, N.E.; Bechtold, L.S.; Kaplan, P.R.; Durbin-Johnson, B.P.; Rocke, D.M.; Rice, R.H. (2022). Witch Nails (Krt90whnl): A spontaneous mouse mutation affecting nail growth and development. PLoS One, 17(11), e0277284. https://doi.org/10.1371/journal.pone.0277284

Thank you to the UF and Penn Vet communications teams, who ALSO collaborated to craft this press release, picked up by P...
12/01/2021
Breakthrough Laminitis Research Opens Potential New Avenues For Treatment - Horse Racing News | Paulick Report

Thank you to the UF and Penn Vet communications teams, who ALSO collaborated to craft this press release, picked up by Paulick Report: https://www.paulickreport.com/horse-care-category/breakthrough-laminitis-research-opens-potential-new-avenues-for-treatment/

Horse owners usually dread hearing the diagnosis of “Laminitis.” The disease plagues horses of many backgrounds, ages and disciplines. Using genetics, UF/IFAS and University of Pennsylvania School of Veterinary Medicine scientists have made a breakthrough in the disease thanks to funding from Th...

Excited to see this collaborative project with Samantha Brooks and Heather Holl at U Florida published. Purified mRNA wa...
11/29/2021
Transcriptome diversity and differential expression in supporting limb laminitis

Excited to see this collaborative project with Samantha Brooks and Heather Holl at U Florida published. Purified mRNA was provided by the Laminitis Discovery Database in the Galantino-Homer Laminitis Lab from supporting limb laminitis (SLL) cases (including samples both from feet with primary, severe SLL of 1-7 days duration and those with very early, often secondary "developmental" SLL) age-matched controls (all Thoroughbreds currently or recently in race training at the time of injury) and the transcriptomic sequencing and data analysis were performed at UF. The results complement and extend our studies of cell stress and stress response and the IL-17A inflammatory pathway in SLL. This project was funded by The Foundation for the Horse (formerly the American Association of Equine Practitioners Foundation).

Edit: Free access for 50 days here: https://authors.elsevier.com/c/1e8apbacHh~3t

Laminitis results in impaired tissue integrity and Inflammation of the epidermal and dermal lamellae connecting the hoof capsule to the underlying dis…

New paper from our group examines the contribution of keratinocyte activation and the IL-17 pathway (important in asthma...
09/21/2021
Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia

New paper from our group examines the contribution of keratinocyte activation and the IL-17 pathway (important in asthma and psoriasis) to inflammation in a model of endocrinopathic laminitis and the ability of distal limb cooling to block it. (free access to this link for 50 days)

The euglycemic hyperinsulinemic clamp model (EHC) of equine endocrinopathic laminitis induces rapid loss of lamellar tissue integrity, disrupts kerati…

Laminitis Lab collaborator, Lynne Cassimeris (Lehigh U) generated this HoofSearch cover art using a lamellar tissue conf...
02/24/2021

Laminitis Lab collaborator, Lynne Cassimeris (Lehigh U) generated this HoofSearch cover art using a lamellar tissue confocal microscopy image with our WGA lectin counterstain and then pseudocolored on her iPad. This and other art is available on many items at the Cassimeris Lab Redbubble shop, 100% of profits go to our collaborative research.

This is actually the abaxial (hoof end) of the lamellae with the hoof wall toward the top of the image and the center of the image being the center of the primary dermal lamella.

The cover of the January 2021 edition of HoofSearch explodes with the neon filtered microscopy of researcher Dr. Lynne Cassimeris of Lehigh University, who captured the stunning detail of a tip of a single lamella from a horse's foot. Inside, listings and links to 83 new peer-reviewed articles published in January are organized by subjects from anatomy to zoo animals. Subscribers: Watch for your link coming this evening!

Our paper on IL-17 signaling in naturally-occurring Supporting Limb Laminitis was published in PLOS One today! This is o...
12/11/2020
Interleukin-17A pathway target genes are upregulated in Equus caballus supporting limb laminitis

Our paper on IL-17 signaling in naturally-occurring Supporting Limb Laminitis was published in PLOS One today! This is open access, so go check it out.

IL-17 signaling is important in a few human diseases you may be familiar with: Psoriasis, psoriatic arthritis, Inflammatory Bowel Disease, and acute lung injury associated with COVID-19. Researchers are suggesting that FDA-approved immunomodulatory drugs that are widely used to treat psoriasis should be used for COVID-19 clinical trials. IL-17 is a biomarker of lung injury in COVID-19, with an area under the receiver operating curve score of 0.926, indicating a very good ability to distinguish between severe and mild COVID-19 cases (Liu, Y et al. 2019-novel coronavirus (2019-nCoV) infections trigger an exaggerated cytokine response aggravating lung injury ChinaXiv (2020).

And if you think that the colorized lamellae shown in Fig 1 would look cool on a cell phone case, t-shirt, mug, etc, go to the Cassimeris Lab Redbubble page for many lamellae-themed holiday gift ideas (100% of earnings go to laminitis research; link in first comment).

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232920

Supporting Limb Laminitis (SLL) is a painful and crippling secondary complication of orthopedic injuries and infections in horses, often resulting in euthanasia. SLL causes structural alterations and inflammation of the interdigitating layers of specialized epidermal and dermal tissues, the lamellae...

We have a pre-print (not yet peer-reviewed, submitted to PLoS One) out on inflammatory pathway signaling in naturally-oc...
04/28/2020
Interleukin-17 pathway activation in Equus caballus supporting limb laminitis

We have a pre-print (not yet peer-reviewed, submitted to PLoS One) out on inflammatory pathway signaling in naturally-occurring Supporting Limb Laminitis cases from the Laminitis Discovery Database. The IL-17 pathway is also active in human psoriasis, inflammatory bowel disease, and equine asthma. In all cases, tissue damage sets off an inflammatory response that sets off a positive feedback loop.

https://www.biorxiv.org/content/10.1101/2020.04.27.063800v1

Supporting Limb Laminitis (SLL) is a painful and crippling secondary complication of orthopedic injuries and infections in horses, often resulting in euthanasia. Due to altered weight bearing, SLL causes structural alternations and inflammation of the interdigitating layers of specialized epidermal....

I'm sure many of you are seeing the horrifying reports about organ failure in severe COVID-19 cases. This is an excellen...
04/20/2020
How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes

I'm sure many of you are seeing the horrifying reports about organ failure in severe COVID-19 cases. This is an excellent article about the current understanding of how the disease may call organ failure. I had not heard about the effect on fingers and toes, but had already been thinking about the parallels with sepsis-associated laminitis. Access to this article is free.

"Reports are emerging of ischemia in the fingers and toes—a reduction in blood flow that can lead to swollen, painful digits and tissue death."

Laminitis Research at New Bolton Center currently involves writing and other remote tasks as the labs are shut down. I have also been making masks for our hospital and essential diagnostic laboratory personnel who are helping to keep our animals and food supply safe. Stay safe and sane. -Dr HGH

https://www.sciencemag.org/news/2020/04/how-does-coronavirus-kill-clinicians-trace-ferocious-rampage-through-body-brain-toes?utm_campaign=news_daily_2020-04-17&et_rid=17052573&et_cid=3290441

The lungs are ground zero for COVID-19, but blood clots may play a surprisingly big role in severe illness

Do you want to support laminitis research AND own some truly unique and functional "equine art"? Laminitis Lab collabora...
03/03/2020
CassimerisLab Shop | Redbubble

Do you want to support laminitis research AND own some truly unique and functional "equine art"?

Laminitis Lab collaborator, Lynne Cassimeris of Lehigh U, has launched a Redbubble page where you can purchase equine lamellar tissue microscopy image-based art on mugs, phone cases, shirts, etc.

100% of proceeds go to Lehigh-Penn collaborative laminitis research projects.

Check it out! Tell your friends!

https://www.redbubble.com/people/cassimerislab/shop?artistUserName=cassimerislab

CassimerisLab is an independent artist creating amazing designs for great products such as t-shirts, stickers, posters, and phone cases.

We are pleased to announce that our paper demonstrating that K124 and K42 are lamellar-specific keratins (the major stru...
09/24/2019
The expression of equine keratins K42 and K124 is restricted to the hoof epidermal lamellae of Equus caballus

We are pleased to announce that our paper demonstrating that K124 and K42 are lamellar-specific keratins (the major structural proteins of the hoof capsule and lamellae) is now published and is freely available at the link below. For the first time in any species, we have produced and validated monoclonal antibodies against a nail unit-specific keratin isoform, K124, which is restricted to the lamellae and absent from the coronet, haired skin, chestnut, tongue, cornea, oral mucosa, and unhaired skin. Current projects are investigating the use of these antibodies in other species and as a lamellar-specific biomarker.

We thank our collaborators at Lehigh University, Cornell University, and University of Florida and the foundations that supported the Laminitis Discovery Database and this study, including the Laminitis Research Fund and Tamworth Trust at Penn Vet, Lehigh University Faculty Incentive Grant, Animal Health Foundation, the American Association of Equine Practitioners Foundation, Grayson-Jockey Club Research Foundation, and the Bernice Barbour Foundation, Inc.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219234

The equine hoof inner epithelium is folded into primary and secondary epidermal lamellae which increase the dermo-epidermal junction surface area of the hoof and can be affected by laminitis, a common disease of equids. Two keratin proteins (K), K42 and K124, are the most abundant keratins in the ho...

I am very pleased to announce that a pre-print (submitted to PLOS ONE, but has not yet been peer-reviewed or accepted fo...
06/20/2019

I am very pleased to announce that a pre-print (submitted to PLOS ONE, but has not yet been peer-reviewed or accepted for publication) of our paper, "The expression of equine keratins K42 and K124 is restricted to the hoof epidermal lamellae of Equus caballus," is available for view/share/comment here:

https://www.biorxiv.org/content/10.1101/678102v1

These keratins are the major cytoskeletal proteins in the hoof lamellae and therefore account for most of the mechanical strength of the epidermal lamellar epithelium. We had first described them in 2010 and have since used several methods to characterize their expression.

We also generated monoclonal antibodies that specifically recognize one of the isoforms, K124, and can be used for future research and diagnostic applications. K124 is found in the secondary epidermal lamellae and is absent from the hoof coronet, haired skin, chestnut, cornea, oral mucosa, tongue, and glabrous skin.

This work represents a multi-year collaboration between investigators at Penn, Lehigh University, Cornell CVM, and the University of Florida, with excellent assistance from genscript.com.

Please share and go to the website to download and comment there. Editors and reviewers pay attention to visits/downloads/comments in determining interest in the submitted paper.

-Dr. Hannah Galantino-Homer

Very short-handed in the lab, but I found some time today to finally provide histopathology images to go along with the ...
06/17/2019

Very short-handed in the lab, but I found some time today to finally provide histopathology images to go along with the earlier post showing normal, “laminitic/sinker” and “laminitic/rotation” feet.

These are typical examples of the microanatomy of feet like those from the Laminitis Discovery Database. As usual, these are meant to be educational, so please share and use, but please attribute to the Laminitis Laboratory at New Bolton Center. – Dr. Galantino-Homer

White asterisk marks the keratinized axis of a primary epidermal lamella in each image. All top images are the same low magnification and all lower images are the same higher magnifications except for the last one on the right, which is higher magnification than the other three.

“Normal”: LAM 84 RF, 2 yr TB gelding with other orthopedic problems. Upper image: Low magnification, lower image: higher magnification.

“Laminitic: Sinking”: LAM 118 LF, 2 yr TB filly with supporting limb laminitis due to a non-weight-bearing injury in the RF. Catastrophic failure of the suspensory apparatus of the distal phalanx with complete stripping of the secondary epidermal lamellar basal cells off of the keratinized axis and suprabasal cells (in other words, failure is mostly occurring between epidermal cells rather than at the basement membrane). Higher magnification image shows basal cells of secondary epidermal lamellae (yellow arrowhead) pulling away from necrotic/cornified suprabasal cells (black arrowhead) and keratinized axis in the less affected RF foot, which was developing secondary supporting limb laminitis.

“Laminitic: Rotation, Lamellar Wedge”: Images on the left are from LAM 140 LF, 14 yr TBxWB mare with PPID/Cushing’s, obesity, and regional adiposity (“cresty neck”). Images on the right are from LAM 109 RF, 9 yr QH mare with equine metabolic syndrome. Both had chronic laminitis with rotation of the distal phalanx relative to the hoof capsule, lamellar wedge, and founder rings. Yellow band indicates widening of the keratinized axis to form “lamellar wedge” of abnormal cornified tissue (lighter pink stain). Green asterisk shows gap with necrotic material and serum that often allows bacteria to track up from the ground surface to cause abscesses, inflammation, and pain. Circles adjacent to serum/necrotic area are forming “cap horn tubules” and contributing to the lamellar wedge. Green arrowhead shows an epidermal island that has detached from a secondary epidermal lamella. Blue arrowheads indicate areas of necrotic/apoptotic lamellar cells and loss of normal microanatomy. These cases were used in our recently published ER Stress in Endocrinopathic Laminitis study.

A slide that I made for a recent Penn Vet Equine Club talk to explain why there are so many laminitis causes. As usual, ...
03/29/2019

A slide that I made for a recent Penn Vet Equine Club talk to explain why there are so many laminitis causes. As usual, please share and copy for educational purposes, as long as you keep the credit at the bottom of the slide.

I find it helpful to consider laminitis as an organ failure of the suspensory apparatus of the distal phalanx, that it occurs when a threshold for laminitis is passed, and that various intrinsic and extrinsic factors can move the lamellae toward the threshold for laminitis (red) or away from it and toward health (green). Some intrinsic factors (in blue) also lower the threshold itself so that a smaller push toward disease is needed to cause laminitis.

Multiple factors can be acting at once and the outcome is determined by their net positive (away from threshold, toward health) and negative (toward threshold) impacts on lamellar tissues.

SADP: Suspensory apparatus of the distal phalanx

Thank you to Paulick Report for reporting on our paper on ER stress in naturally-occurring endocrinopathic laminitis (EL...
02/25/2019
Human Meds May Offer Help To Laminitic Horses - Horse Racing News | Paulick Report

Thank you to Paulick Report for reporting on our paper on ER stress in naturally-occurring endocrinopathic laminitis (EL). Link to the open access paper at the end of the article.

We are currently wrapping up an AAEP Foundation-funded study on ER stress in naturally-occurring Thoroughbred racehorse supporting limb laminitis (SLL) cases. These are very different initiating events, but if you consider it from a cell biology perspective, they could have a common pathway of cell stress due to high insulin (EL) or nutrient starvation (SLL) overwhelming the cell's ability to maintain its normal functions (maintain "homeostasis"), leading to the activation of stress pathways and resulting in changes in the character of the cells (injury response) and/or cell death. Treating the risk factor, high insulin, non-weight-bearing lameness/orthopedic injury, remains the best way to prevent EL and SLL, respectively.
-Dr. Hannah Galantino-Homer
https://www.paulickreport.com/horse-care-category/human-meds-may-offer-help-to-laminitic-horses/

A study team from Lehigh University and New Bolton Center has found a link between cellular stress in laminitis cases and several human illnesses, potentially offering new drug treatments for the disease. In affected horses, the lamellar tissue, which connects the hoof wall to the tissues in the foo...

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Laminitis Research at New Bolton Center

Laminitis Research at New Bolton Center is comprised of the Galantino-Homer Laminitis Laboratory and the van Eps Laminitis Laboratory. These two laboratories have several coordinated projects and also collaborate with other researchers at the University of Pennsylvania School of Veterinary Medicine and Perelman School of Medicine and various institutions across the US.

Laminitis is a common and debilitating disease that affects the epidermal and dermal lamellae of the inner hoof capsule. The lamellae normally allow the transfer of the horse's weight from the skeletal elements of the digit to the hoof wall. Laminitis Research at New Bolton Center was formed in part due to the tragic loss of the 2006 Kentucky Derby winner, Barbaro, to laminitis in January, 2007. Our goal is to better understand laminitis pathogenesis in order to improve the prevention, diagnosis, and treatment of this disease.

Our studies include characterization of the keratin proteins that determine the mechanical properties of the hoof lamellae, identification of diagnostic serum biomarkers for laminitis, the impact of cell stress pathways on laminitis, determining the effects of limb weight-bearing and distal limb cooling on lamellar tissue perfusion, metabolism, and laminitis progression, the molecular mechanism of hyperinsulinemia-induced laminitis, and the investigation of laminitis pathogenesis using transcriptomic, proteomic, and histopathological analysis. The Galantino-Homer Laminitis Laboratory is home to the Laminitis Discovery Database, an archive of pathology images, histology slides, and frozen lamellar tissue and serum from naturally occurring cases of laminitis and unaffected control horses. These materials are being used for several published and ongoing multi-institutional collaborative studies and for educational purposes.

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Comments

I've found that thiamin keeps my previously laminitic horses healthy. Maybe this is why?

https://www.ncbi.nlm.nih.gov/pubmed/7299493

Actually, if you study the consequences of too much potassium you can see that every problem a PPID-horse is experiencing can be explained by excreting this potassium overload. For example:

"Potassium is a well proven insulin secretagogue in the intact organism and the isolated pancreas (12,13). Insulin is a key defender against exogenous potassium load by using intracellular buffering to minimize hyperkalemia before renal excretion"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133473/

The diagram is made from my present hay. Kalium = potassium. The black line represents the need and the green is the content of my hay.

I've also found this.

"In 2 studies on ponies where the K+ intake was only about twice the maintenance requirement, it was found that after a period of 24 weeks K+ output could not counterbalance the intake, leading to K+ retention in the body (Hintz and Schryver 1976; Weidenhaupt 1977)"

"In conclusion, the present study shows that in contrast to ponies, exercising horses can maintain a K+ balance even at high levels of K+ intake by increasing their urinary K+ excretion."

http://onlinelibrary.wiley.com/doi/10.1111/j.2042-3306.1999.tb05257.x/epdf
I hope that someone at New Bolton will read this and give it some serious thought. Over and over, we find that when horses are given species-appropriate care, laminitis goes away. Only when the wrong diet, environment and care is provided does it occurs. Jan trained with Jaime Jackson several years ago and follows the protocols we use for diet, lifestyle, management and trimming.
Question please! Are the changes seen in obese horses and supporting leg laminitis different from endocrinopathic or carb overload cases?
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