December 01, 2020

A high-impact study by a team of Washington University investigators—led by orthopedic chair Regis O’Keefe, MD, PhD, and published in the Proceedings of the National Academy of Sciences—showed that the overexpression of a protein called FoxO1 prevents osteoarthritis in mice.

The important work of this study (available online and featured in Science) has potential to change future care for patients with osteoarthritis.

Researchers at Washington University School of Medicine in St. Louis have discovered that a signaling connection that allows transforming growth factor–β (TGF-β) to protect cartilage from osteoarthritis could direct new clinical care strategies.

“Osteoarthritis, or joint degeneration, is a disease that affects more than 32 million people in the U.S. alone, but it does not have a medical therapy to alter its progression,” said senior investigator Regis J. O’Keefe, MD, PhD, the Fred C. Reynolds Professor of Orthopaedic Surgery and head of the Department of Orthopaedic Surgery. 

Working in a mouse model, O’Keefe and his team found that TGF-β specifically promotes expression of the Fox01 isoform in isolated mouse chondrocytes in a manner that depends on activation of TGF-β–activated kinase 1 (TAK1). Overexpression of FoxO1 in mice protected against experimentally-induced arthritis. The protective TGF-β/TAK1 signaling connection appeared to act in part by activating autophagy (the body’s way of clearing out damaged tissue).

“In other words, maintaining a higher level of autophagy seemed to be beneficial to maintaining these cartilage cells and, thus, maintaining a healthy knee joint,” said co-corresponding author Jie Shen, PhD, assistant professor of orthopedic surgery.

O’Keefe says this finding increases the possibility of delivering FoxO1 to arthritic joints through nanotechnology as a way to regulate autophagy and keep joints healthier, eventually making it possible to prevent or delay millions of future knee and hip replacement surgeries.

»More information is available in Washington University School of Medicine’s newsroom.