Illuminating New Osteoarthritis Drug Targets

Illuminating New Osteoarthritis Drug Targets

22 Dec 2016

Finding new osteoarthritis drug targets is the focus of many researchers including the recently funded Dr. Jenna Galloway. Osteoarthritis is a degenerative disease that gradually destroys cartilage and bone. Normally, cartilage cushions the ends of bones and provides a smooth gliding surface for joint movement. Over time, chronic osteoarthritis, also described as “wear and tear” arthritis, damages the underlying bone and connective tissues, leading to painful swelling, stiffness and limited mobility.

At the Center for Regenerative Medicine and Department of Orthopaedic Surgery at Massachusetts General Hospital, Arthritis National Research Foundation funded researcher Jenna Galloway, PhD, has developed an efficient way to screen a large number of potential new osteoarthritis drug targets with known bioactivity.

“Osteoarthritis has a devastating effect on the musculoskeletal system,” she says. “We need new drugs to prevent or slow the deterioration of joint tissues that occurs in this debilitating disease.”

In her lab, Dr. Galloway is seeking to accelerate the discovery of new pathways to heal damaged joints and regenerate healthy tissue. She began by testing more than 7,000 small molecules, including drugs already approved by the FDA. So far, she has identified over 50 compounds that may promote cartilage and tendon repair.

Can colorful fluorescent fish reveal potential new osteoarthritis drug targets? Do compounds that glow brightly “in a dish” also stimulate cartilage growth in human stem cells?

To illuminate potential drug pathways, Dr. Galloway works with brightly colored, fluorescent zebrafish that have been genetically engineered to glow when viewed under a fluorescent microscope.

By manipulating cells in translucent embryos smaller than a fingernail, she can quickly see which drugs promote cartilage or tendon growth. “When we see an increased number of cells glowing green we know the drug is a cartilage-promoting molecule,” she explains. “When more cells glow red we know the drug is stimulating the growth of tendons.”

Now that the initial screening is finished, Dr. Galloway is collaborating with Arthritis National Research Foundation funded researcher April Craft, PhD, to test the compounds in human stem cells. “We want to assess the potency of these new drugs in humans,” she says. “We will be investigating the underlying mechanism of their activity in human adult stem cells and pluripotent stem cells, cells that can generate into any cell type in the body.”

The next step is to translate discoveries from the chemical screen to treatments for degenerative joint disease. “By integrating drug screening in the fish with human stem cell models, we hope to accelerate the discovery of new pathways with therapeutic potential for joint tissues affected by osteoarthritis,” says Dr. Galloway.

Damage to the joints raises the risk of developing osteoarthritis later in life. Sports injuries often occur when the foot is fixed on the ground and a player suddenly changes direction or stops suddenly, twisting the knee joint. One common reason for joint instability—and later osteoarthritis—is an injury to the anterior cruciate ligament (ACL), the major stabilizer in the knee. More than 100,000 ACL repairs are performed annually in the United States.

“Someday we may be able to engineer cells to improve ligament healing or replace diseased tissues, leading to long-term healthy joint function after injury,” she says. “Our hope is that the drugs we identify could be used in two ways—as therapeutic molecules that stimulate healthy cartilage and tendon and ligament tissues—or in the generation of replacement tissues for damaged tendons, ligaments and cartilage.”

Thanks to her grant from the Arthritis National Research Foundation, Dr. Galloway is eagerly narrowing down the most potent new osteoarthritis drug targets for additional research. “This grant provides critical support for new investigators at a time in their career when funding makes a real difference,” she says. “New treatment options are urgently needed to halt progressive damage to the joint tissues.”