New treatment strategies—such as using MMP inhibitors—may enhance care

“Conventional thinking says that tendinopathy—defined as chronic tendon degeneration—is due to tendon overload, leading to microscopic collagen fiber failure and a failed healing response,” said Scott A. Rodeo, MD, during the 2011 American Orthopaedic Society for Sports Medicine Specialty Day program. “It also says that inflammation is not part of the pathologic process, because inflammatory cells are not seen in biopsies obtained at the time of surgery in patients with tendinosis.”

But according to Dr. Rodeo, of the Sports Medicine and Shoulder Service at the Hospital for Special Surgery (HSS) in New York, recent studies indicate that tendinopathy may be due to mechanical understimulation of tendon cells, rather than tendon overload, and that abnormal differentiation of tendon stem cells may play a role in the development of the condition.

In addition, he noted, there may be an important interaction among load, inflammatory mediator expression, and matrix metalloproteinase (MMP) expression at the microscopic level.

Tendon overload vs. “underload”
According to Dr. Rodeo, recent studies have demonstrated that stress deprivation leads to upregulation of collagenase expression and apoptosis of tendon cells. Research conducted by Steven P. Arnoczky, DVM, and colleagues has shown that tendon fibril injury stimulates local upregulation of collagenase mRNA and MMP-13.

“This collagenase production may weaken the tendon and put more of the extracellular matrix at risk for further damage during subsequent loading,” explained Dr. Rodeo.

More than a decade of research has shown that microscopic collagen fiber failure may play an important role in the development of tendinopathy.

“When microscopic collagen fiber failure occurs,” he explained, “cells in the injured area are exposed to less load; they are deprived of stress. This leads to upregulation of interleukin-1 beta (IL-1β), which is an inflammatory mediator, as well as upregulation of MMPs. The end result is decreased structural and mechanical properties.”

Stem cells
Stem cells may also play a role in the development of tendinopathy. Dr. Rodeo noted that tendon stem cells can differentiate into tenocytes, which lead to tendon repair, or into osteocytes or adipocytes.

“Researchers have found that treating tendon stem cell cultures with prostaglandin E2 (PGE2) induces both adipogenesis and osteogenesis,” he said. “As a result, the number of tenocytes is reduced and fatty and calcified tissues are produced, as seen in tendinopathy.”

An analysis of the effect of mechanical load on tendon stem cells found that when tendon stem cells were stretched, they could continue to differentiate into tenocytes with 4 percent strain. At an 8 percent strain, however, some of the cells differentiated into adipogenic, chondrogenic, and osteogenic lineages. “So, mechanical load clearly plays a role in these pathways,” he concluded.

Inflammatory mediators
According to Dr. Rodeo, the expression of inflammatory mediators may occur in the early stages of tissue injury. He noted that MMPs play an important role in tissue degradation and matrix remodeling and that inflammatory mediator expression can increase MMP activity.

“Imbalances between MMPs and their inhibitors have been implicated in the underlying pathogenesis of tendinopathy,” he said.

For example, when Dr. Rodeo and fellow researchers conducted a study in which they biopsied rotator cuff synovium and bursa at the time of rotator cuff repair, they found increased expression of MMPs and inflammatory mediators, including IL-1β. He added that increased synovial inflammation and tissue degradation correlated with cuff tear size.

Implications for treatment
Future studies about the role of mechanical load may aid in the development of ways to modulate the loading environment to stimulate tissue repair, according to Dr. Rodeo.

“For example,” he said, “eccentric exercise may work via mechanical stimulation, leading to modulation of inflammatory mediators and a shift in the balance of MMPs and catabolic and anabolic gene expression.”

In addition, he said, MMP inhibitors have the potential to prevent ongoing tendon degeneration.

“Some studies have shown that MMP inhibitors can prevent the matrix degeneration that occurs with stress deprivation in rat tail tendon in vitro,” he said. “In addition, MMP inhibitors prevented loss of material properties associated with stress deprivation.

“Therefore,” he concluded, “novel agents that block either inflammatory mediators or MMPs may be effective in treatment of tendinosis.”

Disclosure information: Dr. Rodeo—Pfizer and Cayenne.

Bottom line

• Recent studies have found that mechanical understimulation of tendon cells, rather than tendon overload, may cause tendinopathy and that abnormal differentiation of tendon stem cells may play a role in its development.
• Research also indicates important interactions occur among load, inflammatory mediator expression, and MMP expression at the microscopic level.
• Future studies involving the role of mechanical load may suggest ways to modulate the loading environment to stimulate tissue repair.
• MMP inhibitors may have the potential to prevent ongoing tendon degeneration.

Jennie McKee is a staff writer for AAOS Now. She can be reached at mckee@aaos.org

References

1. Lavagnino M, Arnoczky SP, Egerbacher M, Gardner KL, Burns ME: Isolated fibrillar damage in tendons stimulates local collagenase mRNA expression and protein synthesis. J Biomech, 2006;39(13):2355-2362. Epub 2005 Oct 26.
2. Arnoczky SP, Lavagnino M, Egerbacher M, Caballero O, Gardner K: Matrix metalloproteinase inhibitors prevent a decrease in the mechanical properties of stress-deprived tendons: An in vitro experimental study. Am J Sports Med 2007;35(5):763-769. Epub 2007 Feb 9.
3. Zhang J, Wang J: Mechanobiological response of tendon stem cells: Implications of tendon homeostasis and pathogenesis of tendinopathy. J Orthop Res 2010; May 28(5): 639–643.

Additional resources

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