Osteoarthritis is driven largely by low-grade inflammatory process. The problem may not result from wear and tear, as is generally assumed, according to a study published online Nov. 6 in Nature Medicine.
Researchers have observed certain specialized inflammatory proteins early in the progress of osteoarthritis, before it becomes symptomatic - suggesting that inflammation might be a driver, rather than a secondary consequence, of the disease.
Advertisement"It's a paradigm change," said William Robinson, MD, PhD, the study's senior author, of the implication of the findings. "People in the field predominantly view osteoarthritis as a matter of simple wear and tear, like tires gradually wearing out on a car." It also is commonly associated with blow-outs, he added, such as a tear in the meniscus — a cartilage-rich, crescent-shaped pad that serves as a shock-absorber in joints — or some other traumatic damage to a joint.
The findings offer hope that by targeting the inflammatory processes that occur early on in the development of osteoarthritis — well before it progresses to the point where symptoms appear — the condition might someday be preventable.
Robinson is an associate professor of immunology and rheumatology at Stanford University School of Medicine and a staff physician with the Veterans Affairs Palo Alto Health Care System. The first authorship of the study is shared by research associate Qian Wang, MD, PhD, and Andrew Rozelle, MD, a former Stanford rheumatology fellow now at the Palo Alto Medical Foundation.
It has long been known that osteoarthritic joint tissues host a heightened number of migratory inflammatory cells and of some of the substances these cells secrete — "not nearly as much as in the case of rheumatoid arthritis, which is clearly an autoimmune disease, but enough to make us wonder if inflammation is also a major player in osteoarthritis as well," Robinson said. <
"The new study showed that, indeed, initial damage to the joint sets in motion a chain of molecular events that escalates into an attack upon the damaged joint by one of the body's key defense systems against bacterial and viral infections, the so-called complement system. This sequence of events involves activation of a chain reaction called the "complement cascade," and begins early in the development of osteoarthritis.
The complement system consists of an orchestra of proteins present in blood. Upon activation of the complement cascade — typically, in response to the presence of bacterial or viral infection — these proteins engage in a complex interplay, variously enhancing or inhibiting one another's actions at certain points and culminating in the activation of a protein cluster called the MAC (for "membrane attack complex"). By punching holes in the membranes of bacterial or virally infected human cells, the MAC helps to clear the body of infections.
In their research bioengineered mice lacking a complement-cascade-accelerating protein developed less-severe arthritis, while the mice lacking the complement-inhibiting protein got worse, faster. Thus, mice with impaired complement activation were protected against the development of osteoarthritis in response to meniscal damage.
"Recent findings suggest that low-grade complement activation contributes to the development of degenerative diseases including Alzheimer's disease and macular degeneration. Our results suggest that osteoarthritis can be added to this list of diseases," said Robinson.
Drugs that target the complement system may someday prove useful in preventing the onset of osteoarthritis in people who have suffered joint injuries, Robinson said, though he cautioned that this system is so crucial to our defense against microbial infection that systemic delivery of complement inhibitors would likely not be safe. But it is possible that a brief period of local administration of a complement inhibitor might provide benefit to patients developing osteoarthritis, while minimizing their risk for the development of infections.
"Right now we don't have anything to offer osteoarthritis patients to treat their underlying disease," Robinson said. "It would be incredible, for the one-third of humans over 60 who have it, to find a way to slow it down."
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