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VBCR - June 2015, Volume 4, No 3 - CCR Conference Highlights
Chase Doyle

Despite early and aggressive intervention, remission rates remain low for rheumatology patients; damage is often progressive, morbidity and mortality are significant, and socioeconomic decline is an ongoing concern. The challenges facing translational scientists are vast, but the journey to understand one disorder at the molecular level could provide valuable insights for the future.

“Forty percent of musculoskeletal consults are actually related to tendinopathy,” said Iain B. McInnes, MD, PhD, professor of medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, Scotland. “So we decided to ‘molecularize’ tendon disease...If you knew how to tell a tendon not to go from type I to type III collagen, you would end up with stronger repairs and break the cycle of damage that’s created.”

As McInnes explained at the 2015 annual Congress of Clinical Rheumatology, early changes in the human tendon cause the body to make a value judgment that results in the rapid production of collagen. Because type I collagen, which is very strong, cannot be quickly produced, the body makes type III collagen instead.

“It’s like pitching a tent and constructing a building around the tent,” said McInnes. “Type III collagen is fast, but it’s not very strong, so you get an early repair that’s not useful very long. If you continue to work that tendon, a vicious cycle of damage is created.”

The first step to breaking this cycle was biopsying a torn or partially ruptured tendon in arthroscopic repair. Although this step has been performed numerous times over the years, what McInnes and his team did next has not: they biopsied the opposite tendon as well.

“Because this tendon has come under mechanical stress but has not yet shown any sign of damage, it is therefore the earliest sequence of events that leads to pathology. No one has ever looked at that before,” he said.

The first surprise? It turns out that early tendon disease is very different from established tendon disease. It is an acutely inflammatory lesion full of mast cells, neutrophils, monocytes, and T cells.

“Early tendinopathy is a bona fide inflammatory disease,” said McInnes, “every bit as inflamed as a lot of synovitis.”

Pathogenesis-Led Discovery


While basic scientists might be tasked with pursuing single pathways, McInnes and his team “follow the disease” in a pathogenesis-driven approach to discovery.

“I’m a translational biologist,” he said. “I don’t have the luxury of going after pathways just because they’re there.”

Thus, the most important questions for his team were: (1) What is the sequence of events that lead to improper healing in the tendon; and (2) If you target the relevant tissue, does it make a difference?

What they discovered, using mouse models to mimic early tendon damage, was a molecule called interleukin 33 (IL-33), which was functionally and temporally related to type III collagen production. In other words, neutralizing IL-33 regulated the levels of type III collagen. In a complicated process involving microRNA delivery vehicles, researchers were able to “switch off” the production of type III collagen and revert back to type I for healthy, strong, and rapid tendon repairs.

Future Implications


Could tennis players inject themselves with monoclonal antibodies before a match one day to stave off inflammation? Given the constant microprocessing and microtearing of tissues, the notion might not be as far-fetched as it sounds.

“I’m not sure I would do it in everyone before they play tennis,” said McInnes, “but for those people who have a tendency of developing tendinopathy, then absolutely—there might well be prophylactic normal- tendon modulation.”

For now, McInnes and his team are betting on horses.

“We have clinical trials beginning with racehorses now,” he concluded. “Twenty-five percent of racehorses actually develop career-threatening tendinopathy, so we’re seeing if we can change that first.”

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