A molecule with big promise in arthritis treatment

<b>DR. GREGORY JAY,</b> an emergency room physician at Rhode Island Hospital, is developing a new approach to the treatment of joint injuries and arthritis. /
DR. GREGORY JAY, an emergency room physician at Rhode Island Hospital, is developing a new approach to the treatment of joint injuries and arthritis. /

A research team led by a Rhode Island Hospital emergency room doctor has made a discovery about the nature of wear in joints that could result in the development of a new drug treatment for sprains and arthritis.
Gregory Jay, who is an associate professor at Brown University’s Warren Alpert Medical School in addition to his work at Rhode Island Hospital, led research that linked early wear in joints with an absence of lubricin, a naturally occurring molecule that acts as a lubricant, reducing friction between opposing layers of cartilage.
The discovery also suggests that lubricin or a lab-produced derivative could be used as a preventive treatment that could reduce the need for painful and costly joint replacement surgery. Arthritis and sports injuries damage the joints of thousands of people in the United States and millions of people worldwide each year.
While doctors have known that increased friction inside of joints causes wear that eventually contributes to arthritis, researchers have not been able to identify the molecules responsible for keeping joints lubricated.
In fact, the discovery provides strong evidence that hyaluronic acid, the current drug of choice for arthritic joints, is actually not the most effective method for lubricating joints, Jay said.
“Everybody thought for years that hyaluronic acid is the joint lubricant,” said Jay, who recently published his findings in the academic journal Arthritis & Rheumatism. “It looked like a lubricant – it was slimy, it was viscous, therefore it had to be a lubricant. But it’s not that way at all. It’s absolutely untrue.”
If hyaluronic acid-based drugs increase viscosity in injured or arthritic joints at all, they do so by reducing inflammation, Jay said. The “inflammation cascade” that occurs inside injured joints releases enzymes that metabolize, or digest, the joint’s natural lubrication.
The discovery has significant clinical and commercial implications for the multimillion-dollar visco-supplementation industry, which has been dominated by hyaluronic acid-based drugs since the U.S. Food and Drug Administration approved their use in 1994. Five drug makers, including Genzyme and Johnson & Johnson, currently market joint treatments derived from hyaluronic acid, Jay said.
Jay is working to develop a new drug that could be injected directly into hips, knees and other injured or arthritic joints that would combine hyaluronic acid with lubricin to replace the naturally occurring lubricant that lessens or disappears following an injury.
Aside from treating sprains and existing arthritis, the drug could potentially prevent arthritis, Jay said. Past research already has suggested a link between traumatic joint injuries and the onset of early osteoarthritis, he said.
“It’s after an injury when you actually see the lubricating ability diminish,” Jay said. “So the strategy would be to put a lubricant back in, but also inhibit the inflammatory cascade at the right points so that you can preserve the lubricant that you put back into the joint.”
Through Rhode Island Hospital, Jay has filed two patents related to his lubricin discovery, and he is currently conducting studies in mice that he hopes will result in the development of a new injection treatment for inflamed joints that would be marketed by Tribologics, a Wellesley, Mass.-based biotech company that Jay formed in 2004.
“It’s something we’re exploring,” he said. “The protein can be made, and at this point we’re doing animal studies, trying to see if we can protect cartilage.”
Jay has studied lubricin’s role in lubricating joints for two decades. In the latest research, he and a team of scientists from Brown, Rhode Island Hospital, Case Western Reserve University, the University of Kuopio in Finland, Boston Children’s Hospital and Harvard Medical School were able to show for the first time how lubricin works at a molecular level to lubricate joints.
At the nanoscale, lubricin appears as a mesh of interlocking fibers that holds water and contains an electrical charge, repelling opposing layers of cartilage.
Jay and his team made the discovery by studying cartilage from the knees of mice that don’t produce lubricin. Directly after birth, the cartilage was smooth. But in as little as two weeks, researchers found, the cartilage began to show signs of wear.
Under an electron microscope, scientists could see that the collagen fibers that cartilage is composed of were breaking up, giving the surface a rough, frayed appearance – the first signs of joint disease or injury. •

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