Osteoarthritis is generally thought to result from long-term wear and tear on joints, but a new study provides strong evidence that low-grade inflammation plays an important role in causing it.
Osteoarthritis is generally thought to result from long-term wear and tear on joints, but a new study provides strong evidence that low-grade inflammation plays an important role in causing it. The findings, published online earlier this week in Nature Medicine, could lead to new therapies that target the inflammation early and prevent the development of osteoarthritis.
Migratory inflammatory cells and some of the substances they secrete have long been detected in osteoarthritic joint tissues in numbers high enough to make researchers wonder whether inflammation might play a role in causing the condition. When the researchers behind the current study detected increased numbers of specialized inflammatory proteins at an early, asymptomatic point in the process of osteoarthritis, they realized that the inflammation might be a cause rather than a secondary consequence of the disease.
The new study finds that initial damage to a joint sets in motion a chain of molecular events that grows into an attack on the damaged joint by a process known as the “complement cascade,” one of the body’s key defenses against bacterial and viral infection. Under normal circumstances, the complement cascade activates proteins that punch holes in the membranes of cells infected with a bacteria or virus to clear the body of the infection.
An early clue to the role of the complement cascade in osteoarthritis came when researchers discovered that tissues of osteoarthritis patients had high levels of the proteins involved in accelerating the cascade and low levels of the proteins involved in slowing it down. To further explore, researchers inflicted meniscal tears and removal—the sort of joint damage that typically leads to osteoarthritis—on mice. The procedure was done on normal mice and on three strains of bioengineered mice: two missing proteins that accelerate the complement cascade and one missing a protein that slows it.
The normal mice developed osteoarthritis at the expected level; the mice missing the accelerating protein developed less severe arthritis; and the mice missing the braking protein developed more severe arthritis. Additional experiments found that MAC (membrane attack complex), a key component of the complement cascade, binds to cartilage-producing cells in joint tissues and causes them to secrete more proteins involved in the complement cascade and other inflammatory chemicals and enzymes that eat up cartilage in the space between cells.
The researchers hope that drugs that target the complement cascade without unduly disabling the body’s immune defenses will be developed that can slow or stop the progress of osteoarthritis. “Right now we don’t have anything to offer osteoarthritis patients to treat their underlying disease,” said the study’s senior author, William Robinson, MD, PhD, an associate professor of immunology and rheumatology at Stanford University School of Medicine, in a press release. “It would be incredible, for the one-third of humans over 60 who have it, to find a way to slow it down.”