Naturally Occurring Enzyme Found to Restore Functionality in Slow-to-Heal Connective Tissue
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Whether from a sports collision, a household mishap or years of chronic overuse, tendon injuries are both common and hard to repair. Now, a University of Maryland-led research team is developing a novel method to restore or improve tendon functionality using a naturally occurring enzyme in the body.
The group’s findings, published last month in Frontiers in Bioengineering and Biotechnology, could one day lead to therapies to treat acute and chronic connective tissue injuries.
Each year, more than 30 million musculoskeletal injuries occur in the United States alone, and roughly half of them are to tendons and ligaments, according to a study published in the Journal of Hand Surgery. Tendons are a fibrous tissue that consists largely of collagen proteins and water and attach muscles to other parts of the body—namely, bones—that allow us to move when muscles contract and relax.
But unlike muscles, tendons have little blood supply, so injuries can require significant time and rehabilitation to heal, and they often do not regain their full strength and are susceptible to reinjury and chronic pain.
Fischell Department of Bioengineering Associate Professor Catherine K. Kuo is working with members of her Developmental and Regenerative Engineering Lab to develop an approach that might one day lead to the first tendon-specific therapeutics in medicine. That could make a difference for millions of people, Kuo said.
“Because tendons are so prone to wear and tear, people of all walks of life are susceptible to tendon injuries,” said Kuo, who holds secondary appointments with the University of Maryland, Baltimore’s School of Medicine and the UMD Biophysics Program. “Whether you’re a professional or college athlete, an office worker who spends many hours each day on a computer, or a senior who is enjoying retirement, your quality of life could be impacted by a tendon injury leading to chronic inflammation and pain, or even complete disability.”
Kuo’s technique centers on promoting a process known as crosslinking—or binding—of collagen molecules, which play a critical role in tendon mechanical properties, development and repair.
Previous studies have proposed ways to ramp up the process to facilitate repair, but they’ve used crosslinking agents that are not naturally present in the body and have harmful effects at the concentrations needed.
In search of a more promising option, Kuo and her team investigated how tendons are naturally strengthened during development, starting with the embryo. Her lab discovered that lysyl oxidase (LOX), a naturally occurring enzyme, is a critical regulator of tendon mechanical properties during new tissue formation. LOX drives the formation of crosslinks between collagen molecules, including the kinds that are most prevalent in tendons.
Building on an earlier discovery that inhibiting LOX during tendon development negatively impacted elasticity, Kuo and her team examined the effects of engineered LOX (rLOX) treatment on chick embryonic tendons at different developmental stages, demonstrating that rLOX treatment can induce additional collagen crosslinking and thus restore the tendon’s mechanical properties.
Concerned that applying too much rLOX might over-stiffen tendons, Kuo and her team tested varying concentrations of rLOX. They discovered that was not the case, and that higher concentrations of rLOX led to a plateau in crosslinking levels and that the mechanical properties remained within natural levels.
In addition to poor tendon healing, abnormal LOX-mediated collagen crosslinking plays a significant role in heritable connective tissue disorders and birth abnormalities that affect tendons, including Ehlers-Danlos syndromes and clubfoot.
Moving forward, Kuo and her team plan to test their approach in adult mammalian tendons to see if rLOX treatment can restore the natural mechanical properties of healthy adult tendons. The group also plans to test whether rLOX can do this without causing unwanted side effects within tendon cells or tissue, Kuo said.
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