If you ever took a high school biology class, or if you're a horseman used to hearing a veterinarian review bloodwork, you may be familiar with macrophages or monocytes – and chances are, you think of them as bearers of bad news.
Recent studies on these cells found that the oft-maligned macrophages are vital for joint health and may provide the key to the treatment of joint disease in horses, according to Dr. Bruno Menarim, a researcher in the Gluck Equine Research Center's Musculoskeletal System Lab, that have dedicated several years to this field.
Macrophages are cells which are often abundant in inflamed areas. For a long time, we knew that macrophage-like cells existed in the healthy synovial (joint) membrane, but aside from signaling a problem and “cleaning the joint,” scientists weren't sure they did anything productive. We even thought, mistakenly, that they were causing problems. Now, Menarim says, we know that they are the source of key molecules for adequate joint function and cartilage metabolism.
When he began his research career, Menarim was focused on how the cells that emerge from “carving” the bone under the damaged cartilage improved healing of cartilage defects. He was surprised to discover that when these cells emerging from that bone marrow gained contact with the viscous synovial fluid in the joint, over 70% became macrophages. Even more interestingly, the number of macrophages was four times higher if the synovial fluid was inflamed.
Menarim began questioning about what macrophages do in joints, particularly arthritic joints, and how learning about it could improve joint therapy.
“Some research groups had shown that if you deplete macrophages from inflamed joints there was a dramatic clinical improvement,” he said. “So, they thought they had a treatment for arthritis.”
It didn't take long however for researchers to realize that in fact when they removed macrophages from an inflamed joint, clinical signs may temporarily improve but the progress of the arthritis hastened. The removal of joint macrophages also eliminated macrophage-derived molecules that were key for cartilage and overall joint maintenance.
“Right there was clear evidence that we should better understand the roles of macrophages in joint function and harness them as treatment,” said Menarim.
Macrophages live in all types of tissue – skin, brain, bone, lungs, etc. They stick around as sentinels, guarding tissue integrity and take fast action if something goes wrong. When the body detects damage, they flood the area to counteract aggressors and provide a protective shield around damaged tissues inside the body, like a skin wound scab, under which they orchestrate tissue repair. They are essential to drive proper healing and resolve inflammation. When macrophages are overwhelmed by the task at hand, they stimulate more inflammation to help recruit more healing molecules to the area – that's why you'll see their numbers increase as an injury flares. Without macrophages, an injury can't heal properly and may only form a dysfunctional scar or set the stage for chronic inflammation.
Menarim and collaborators found that macrophages in arthritic joints have lost some of their normal ability to do housekeeping functions that are essential to resolve inflammation – which makes sense, since osteoarthritis is a condition derived from chronic inflammation. He also found that collecting macrophages from the bone marrow and injecting them in either acute or chronically inflamed joints dramatically helped the inflammation resolve, while joints that did not receive macrophages remained inflamed.
Upon further study, the researchers identified several mechanisms by which these macrophages produced such remarkable effect. With support from the University of Kentucky and several industry stakeholders, Dr. Menarim and collaborators are now working on synthetic molecules to mimic the response of macrophages to reproduce those outstanding results.
His goal is to create an off-the-shelf product that veterinarians could use to do a better job of addressing the root causes of the inflammation leading to osteoarthritis – ineffective inflammation resolution. Therapies promoting inflammation resolution can produce clinical results comparable to that from corticosteroids, but without the side effects.
“Inflammation resolution and anti-inflammation are two very different things,” Menarim said. “Inflammation resolution is not a passive termination of inflammation; it's an active phenomenon that is built by macrophages in the joint, which use some byproducts of the inflammatory response to resolve inflammation.
“Anti-inflammation is simply blocking a pro-inflammatory response. That's what anti-inflammatories do. If we use an anti-inflammatory and block that pro-inflammatory response, we are also blocking the production of building blocks of a resolution response. And often that predisposes to chronic inflammation.”
Anything that could reduce the reliance on anti-inflammatory drugs could prove beneficial for equine welfare and the horse industry long-term. A product designed to do the work of macrophages could also treat the root causes of some inflammatory conditions instead of simply treating symptoms.
Menarim is keen to emphasize that such a product could meet important needs in the current equine veterinary landscape and could become a powerful tool in a veterinarian's toolbox when dealing with chronic inflammation.
“It won't be the magic cure for every problem or every horse. We've also got a while to wait for it as the science behind of it is being refined” he said.
Think of the maligned macrophage as a soldier fighting a war on inflammation. Instead of stunting their progress, it may be better to work with them.
“If you strengthen your army, it will perform better, and you might win the war,” he said.
Learn more about this research in the World Journal of Stem Cells
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