Scientists Explore Role of COX-2 in Fracture Healing

Fracture or break a bone, and you pop an ibuprofen. Research being conducted at the University of Rochester Medical Center calls that common practice into question. In an article just published in the June issue of the Journal of Clinical Investigation, scientists at the University's Center for Musculoskeletal Research have for the first time identified that the enzyme cyclooxygenase-2 (COX-2) plays an essential role in bone formation during skeletal repair.

Over the past 18 months, several research studies had begun to document a link between delayed fracture healing and anti-inflammatory medications, but no one had yet figured out why this correlation existed. The University of Rochester scientists set out to uncover the common link between anti-inflammatory medications and bone healing. The investigators showed that the ability of stem cells to form bone cells, a critical event in bone repair, is impaired in the absence of the enzyme COX-2. In a series of tests in mice, the scientists further showed that fracture healing was significantly delayed in COX-2-deficient mice as compared with control mice. For example, 8 of 10 control mice showed bone union on x-rays compared with only 3 of 8 COX-2-deficient mice.

"Our research for the first time pinpoints the unique mechanism of COX-2 in bone repair," Regis O'Keefe, M.D., Ph.D., professor, Department of Orthopaedics at the University of Rochester Medical Center, said. "This study raises concerns regarding the use of COX-2 inhibitors in patients who suffer from bone fracture or who are undergoing other types of bone repair."

More than 12 years ago, researchers at the University of Rochester discovered the gene in humans that is responsible for producing the COX-2 enzyme and revealed the enzyme's role in causing inflammation within individual cells. The team, lead by Donald Young, M.D., a physician and biochemist, provided the basic understanding of the role of COX-2 in disease and showed that selectively blocking the activity of the COX-2 enzyme would be beneficial in treating inflammation. COX-2 has been the subject of intense study in recent years for its apparent role in diseases like arthritis, cancer, and Alzheimer's disease. Most aspirin and anti-inflammatory medications inhibit both COX-2 and its related gene, COX-1, to ease pain and inflammation.

O'Keefe added that until further research is done, no one should stop taking medications prescribed by their physicians.

The work was supported by research grants from the National Institutes of Health, the Orthopedic Research Education Foundation, and the Musculoskeletal Transplant Foundation. The complete abstract is available at http://www.jci.org/cgi/content/full/JCI200215681v1.