Role of immune system in joint disease in horses highlighted in review

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Role of synovial resident macrophages and inflammatory macrophages in joint health and osteoarthritis. This figure illustrates the complex interaction between endogenous self-renewing synovial cell macrophages, which exist as M2 cells in the healthy joint, and the inflammatory macrophage M1 population recruited from inflammatory monocytes in blood in response to chemokines produced during joint inflammation occurring during the progression of OA.
Role of synovial resident macrophages and inflammatory macrophages in joint health and osteoarthritis. This figure illustrates the complex interaction between endogenous self-renewing synovial cell macrophages, which exist as M2 cells in the healthy joint, and the inflammatory macrophage M1 population recruited from inflammatory monocytes in blood in response to chemokines produced during joint inflammation occurring during the progression of OA. McDermott, Pezzanite et al

The role of the innate immune system in the development of osteoarthritis in horses and humans has been increasingly recognised in recent years, according to the authors of a just-published review.

Osteoarthritis is one of the most common causes of joint disease in many species, including horses and humans. About 30.8 million people in the United States — 13.4% of the adult population — suffer from the condition, resulting in $US185 billion in medical costs annually.

Similarly, in horses, osteoarthritis is considered the most common cause of lameness, accounting for about 60% of the caseload presenting for soundness evaluations.

Research suggests the direct and indirect medical costs associated with osteoarthritis to be between $3000 and $15,000 per horse each year in the US alone. Up to 66% of Thoroughbred racehorses develop the disorder, resulting in pain and significantly shortened careers.

Juan Estrada McDermott and his fellow researchers at Colorado State University, writing in the journal Animals, said osteoarthritis can be viewed as a condition caused by several factors, such as age, acute trauma, and/or irregular or repetitive overload of joints. Each can produce a progressive deterioration of cartilage surfaces, as well as soft tissue and bone remodeling.

The condition is characterized by low-grade chronic joint inflammation resulting from, and continually fueling, physical damage of joint surfaces and joint degeneration as a whole.

They said the chronic form has classically been considered a non-inflammatory degenerative condition but, as recent research suggests, it is much more complex than a simple “wear and tear” or aging phenomenon.

Recent work highlights the hypothesis that innate inflammation is driven to a large extent by synovial macrophages, blurring the demarcation between definitions of inflammatory versus degenerative diseases.

Macrophages are among the cell types present in joints that, when activated, can play a role in regulating the inflammatory reaction. The review team described macrophages as central players in host defense.

They are distributed in almost all tissues, having unique functions in each organ. In addition to their more familiar functions as proinflammatory, scavenger, antimicrobial, and antitumor defense effector/mediators, macrophages also function as immune modulators, promoting anti-inflammatory and tissue repair processes.

“Given their central role in osteoarthritis, a clinical approach targeting activated macrophages at an earlier stage of osteoarthritis may serve to inhibit or slow the progression of disease,” the review team said.

Immune events in osteoarthritis involve not only joint cartilage but also the synovium, adipose tissues, and subchondral bone.

They said understanding the molecular, cellular, and tissue relationships driving progressive joint degradation in osteoarthritis remains incomplete, and repair or regeneration of full-thickness articular cartilage poses a particular orthopedic challenge.

From an anatomical perspective, the horse model of osteoarthritis most closely resembles humans with regard to articular cartilage thickness.

In addition, horses suffer from osteoarthritis frequently and spontaneously, providing veterinarians with significant experience in treating the condition.

They said although there is a strong correlation between obesity and chronic inflammation in humans and mice, such a comparison has not been made for horses. It is likely that post-traumatic injury is the more common cause in horses.

The review team traversed the immunomodulatory therapies employed against osteoarthritis in equine practice, including the use of mesenchymal stromal cells, gene therapy and corticosteroids.

They said current studies by members of the review team point to the important role of innate immunity in joint disease progression in horses, as well as the opportunity for potential targets for regenerative therapies.

Studies show that osteoarthritis is a progressive disease that involves macrophages, leading to macrophage-related inflammation and degradation of local cartilage, the review team concluded.  “It is apparent that low-level, sustained innate immunity in joints contributes to the development of progressive osteoarthritis.”

Improved understanding of the role of the innate immune system in the development of the condition, particularly in the early stages of disease, will undoubtedly lead to new immune-modulatory approaches to manage it.

Importantly, targeting the pro-inflammatory cascade in osteoarthritis may lead to the development of novel therapeutic strategies focused on re-establishing immune balance in the joint, they said.

“The key cells in all these processes, monocytes and macrophages, are the most important target for these new therapeutic approaches,” they said.

“On the basis of our clinical experience, more pre-clinical animal models and clinical trials are necessary to evaluate the role of immune cells such as macrophages as selective targets in earlier stages of osteoarthritis in the prevention and treatment of the disease.”

They said the development and testing of biological therapies such as mesenchymal stromal cells in equine patients prior to use in humans hold tremendous potential for short and long-term translational benefits in combating the condition.

The review team comprised McDermott, Lynn Pezzanite, Laurie Goodrich, Kelly Santangelo, Lyndah Chow, Steven Dow and William Wheat.

Estrada McDermott, J.; Pezzanite, L.; Goodrich, L.; Santangelo, K.; Chow, L.; Dow, S.; Wheat, W. Role of Innate Immunity in Initiation and Progression of Osteoarthritis, with Emphasis on Horses. Animals 2021, 11, 3247. https://doi.org/10.3390/ani11113247

The study, published under a Creative Commons License, can be read here

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