Eureka! Rush Researchers Find Breakthrough in OA

Researchers at Rush University Medical Center, in collaboration with researchers at Northwestern University, have identified a molecular mechanism central to the development of osteoarthritis (OA) pain. An article describing the research was published in the December 11 print version of the Proceedings of the National Academy of Sciences.

“Clinically, scientists have focused on trying to understand how cartilage and joints degenerate in osteoarthritis. But no one knows why it hurts, ” said Anne-Marie Malfait, M.D., Ph.D. in the December 27, 2012 news release. Dr. Malfait, who led the study, is associate professor of biochemistry and of internal medicine at Rush.

Dr. Malfait and her colleagues, using a surgical mouse model, were able to monitor development of both pain behaviors and molecular events in the sensory neurons of the knee and correlate the data from repeated observations over an extended period.

“This method essentially provides us with a longitudinal ‘read-out’ of the development of OA pain and pain-related behaviors, in a mouse model, ” Dr. Malfait said.

The researchers found that a chemokine known as monocyte chemoattractant protein (MCP)-1 (CCL2) and its receptor, chemokine receptor 2 (CCR2), are central to the development of pain associated with knee OA. Monocyte chemoattractant protein-1 regulates migration and infiltration of monocytes into tissues where they replenish infection-fighting macrophages. Previous research has shown that MCP-1/CCR2 are central in pain development following nerve injury.

In the study, following surgery the laboratory mice developed mechanical allodynia that lasted 16 weeks. Levels of MCP-1, CCR2 mRNA and protein were temporarily elevated, and neuronal signaling activity increased in the DRG at eight weeks after surgery. This result correlated with the presentation of movement-provoked pain behaviors (for instance, mice with OA travelled less distance, when monitored overnight, and climbed less often on the lid of their cage—suggesting that they avoid movement that triggers pain) which were maintained up to 16 weeks.

Mice that lack CCR2 (knockout mice) also developed mechanical allodynia, but this began to resolve from eight weeks onward. Despite having severe allodynia and structural knee joint damage equal to that in normal mice, CCR2-knockout mice did not develop movement-provoked pain behaviors at eight weeks.

“Increased expression of both MCP-1 and its receptor CCR2 may mediate increased pain signaling through direct excitation of DRG neurons, as well as through attracting macrophages to the DRG, ” the researchers said.

“This is an important contribution to the field of osteoarthritis research. Rather than looking at the cartilage breakdown pathway in osteoarthritis, Dr. Malfait and her colleagues are looking at the pain pathway, and this can take OA research in to a novel direction that can lead to new pain remedies in the future, ” said Joshua Jacobs, M.D., professor and chairman of orthopedic surgery at Rush University Medical Center.