Gone Fishing: Zebrafish Studies May Lead to New Treatments for Osteoarthritis

Cut a finger and the wound scabs over and heals itself. Break a leg and new bone fills in the gap. So why are joints debilitated by osteoarthritis so bad at repairing themselves? A tiny, striped, freshwater fish native to South Asia—the zebrafish—may hold the answer.

“Zebrafish are amazing,” says Joanna Smeeton, PhD, the H.K. Corning Assistant Professor of Rehabilitation and Regenerative Medicine Research at Columbia University Vagelos College of Physicians and Surgeons, who has built her research career around this model organism in search of treatments for osteoarthritis, a leading cause of disability in the United States.

“These fish seem to be able to regrow everything: fins, heart cells, spinal tissue, cartilage, ligaments. They have this broad-spectrum regenerative capacity.”

The zebrafish’s uncanny capacity for renewal appears to lie in its stem cells. “If we can understand how those cells contribute to joint repair, we may be able to awaken similar cells in humans to improve the repair of joints damaged by injuries or degenerative diseases,” she says.

Yes, zebrafish get arthritis

Smeeton became smitten with the fish as a postdoc investigating skeletal development at the University of Southern California. Since the 1970s, researchers have been using zebrafish to investigate everything from birth defects to muscular dystrophy to Alzheimer’s.

One of the more remarkable attributes of zebrafish is that their embryos are transparent and develop outside the mother, providing a literal window onto various developmental processes. Their genes are similar to those of humans and highly modifiable. What’s more, these little fish—roughly the size of a AAA battery—are easy to raise and quick to reproduce.

But until Smeeton’s postdoctoral work, osteoarthritis researchers had to look elsewhere for an experimental model. Zebrafish joints were thought to lack lubricin, a lubricant that protects the joints of land-dwelling creatures against the forces of gravity and general wear and tear. In their weightless aquatic environment, fish would seemingly have little need for such lubrication, making them a poor model for human joint disease.

But this argument made little sense to Smeeton and her colleagues. “There’s more to joint biomechanics than gravity,” she says. “We reasoned that swimming puts a lot of pressure on the zebrafish skeleton, so we thought, maybe their joints aren’t all that different from ours,” she says. Digging deeper, they found scant evidence in the scientific literature that zebrafish joints weren’t lubricated. Then, using advanced imaging and genetic analyses, Smeeton and her colleagues demonstrated that zebrafish do produce a form of lubricin, especially in the jaw and pectoral fins. Deletion of the lubricin gene resulted in the same age-related degeneration of joints seen in humans.

The findings, reported in eLife, pushed back the evolutionary origins of lubricated joints millions of years. More importantly, they gave researchers a new model for studying the cells and molecules that drive osteoarthritis and the cells and molecules that can reverse its effects.

Identifying healing cells

“That discovery spring boarded me into arthritis research,” Smeeton says. It also helped her win a prestigious “Pathway to Independence” K99/R00 award and, in 2022, a “New Innovator” award from the NIH’s “High-Risk, High-Reward” program, which supports exceptionally creative early career investigators who propose innovative, high-impact projects.

The stakes are huge. Some 32.5 million Americans have been diagnosed with osteoarthritis, according to the Centers for Disease Control and Prevention. Existing treatments can reduce symptoms, but they do nothing to addresses the condition’s root causes.

At Columbia since 2020, Smeeton is studying how stem cells contribute to the regeneration of cartilage and ligaments in the zebrafish jaw. “We’re asking such questions as: What types of cells are involved in tissue repair? Where do they come from? How do they work together?” Her lab recently reported in npj Regenerative Medicine that injury induces mature ligament cells to dedifferentiate and contribute to the pool of stem cells to rebuild ligaments.

She has also expanded her research to include studies of how zebrafish rebound from major joint trauma without creating scars, identifying diverse cell populations involved in cartilage and ligament repair.

Smeeton joined the Columbia faculty partly because of its Stem Cell Initiative. “I wanted to be involved in a vibrant research community where I could get different perspectives of stem cell biology and elevate my work to the next level.”

Weeks after her arrival at Columbia, the pandemic hit New York City, shutting down her lab before she had a chance to fill it with staff and equipment. “It was an interesting way to start a career with new colleagues at a new institution,” she says.

Add to that the challenge of parenting twins (a boy and a girl now age 7) in a big new city. “The pandemic sort of quashed all my hobbies,” says Smeeton, an avid hiker and singer. “Now my hobby is figuring out the New York educational system.”