It’s long been held that OA is a result of wear and tear on the joints, an inevitable consequence of years of use. But increasingly research is painting a far different picture – a disease resulting a complex interplay of multiple factors, including genes, body fat, trauma and, of course, aging. 

Here are some of the factors now known to be involved in osteoarthritis and what these findings could potentially mean for treatment. 

Genes

In 1990, the National Institutes of Health announced that scientists had isolated a gene responsible for osteoarthritis. The flawed gene is involved in making type II collagen, a key component of joint cartilage. In people with the gene mutation, weakened cartilage leads to a form of familial osteoarthritis that occurs in early adulthood.

Since that time, scientists have discovered that this type II collagen gene is not the gene responsible for osteoarthritis, but is likely just one of many – some which are not directly involved in joint cartilage, says Roland W. Moskowitz, MD, of Case Western Reserve University in Cleveland, one of two scientists making that first genetic discovery. 

For example, joint laxity in a condition called Ehlers-Danlos syndrome could lead to problems with the articular cartilage, resulting in secondary OA, as could certain genetic metabolic disorders such as hemochromatosis – a genetic disease in which too much iron builds up in the body – or calcium pyrophosphate dihydrate (CPPD) deposition disease, a condition in which CPPD, a calcium salt, builds up and the joints and forms irritating crystals.

Research shows genes also play a role in OA severity. Most recently, data from the Johnson County Osteoarthritis Project – which monitored 1,154 residents of the North Carolina county for up to 11 years – revealed nine genes associated with the progression of osteoarthritis. The strongest of the associations involved a pattern of variations in the gene for interleukin-1 receptor antagonist (IL-1RA), a cytokine associated with inflammation and cartilage breakdown, says Joanne M. Jordan, MD, director of the University of North Carolina’s Thurston Arthritis Research Center, who led the study.  Having the variations doubled the chance of a person’s OA progressing to a severe stage, she says. 

While similar findings have occurred in some other studies, not all have identified the same genetic variants to be associated with knee OA progression. Jordan says despite this, genetic findings may offer clues for understanding and treating the disease and help doctors identify patients whose disease should be treated more aggressively.

Body Fat

Just like heavy loads can cause your car’s tires to wear faster, carrying too much weight on your frame can wear your cartilage faster, particularly if your joints are out of alignment. But research in recent years has revealed the obesity/OA connection goes beyond the stress additional weight places on joints. Researchers now know that fat tissue releases inflammatory chemicals that affect the joints.

One key suspect is leptin, a hormone produced by fat cells that plays a key role in regulating appetite, says Farshid Guilak, PhD, director of orthopaedic research at Duke University. Scientists have found higher levels of leptin in samples of diseased joint cartilage compared with healthy cartilage. Furthermore, leptin levels in the joint correspond with the level of damage.  Several studies have also found that leptin levels correlated with pain levels reported by patients with OA.

To better understand the role of leptin in OA, Guilak and his colleagues studied mice engineered to lack either leptin or leptin receptors on cells. “Leptin circulates through the body, but acts in the brain to control appetite,” says Guilak, whose study was funded by the Arthritis Foundation. “To control appetite it has to bind to leptin receptors on a cell – it has to dock.” Without leptin or its receptors, the mice grew to four times the normal weight of mice, but surprisingly they did not develop osteoarthritis.

Further research by the team showed that normal mice fed a high-fat diet weighed far less than leptin-deficient mice, but did develop arthritis. “This leads us to think it may be something about the leptin molecule itself that is causing osteoarthritis,” says Guilak. “Leptin, even though it controls appetite, may actually have inflammatory effects.”

Another explanation is a high-fat diet – rather than the weight gain it tends to cause – is responsible. “If we feed mice the diet that has saturated fats and lard in it, the fatty acids themselves can be inflammatory.”

Trauma

When a bone is injured, it often mends quickly with no further problems. But unlike bone and most other tissues, articular cartilage lacks blood vessels, nerves and lymphatics, channels that carry lymph – a clear fluid that bathes and nourishes body tissues. As a result, injured cartilage doesn’t heal well.

Damage to the joint can lead to joint instability, which can cause cartilage to wear excessively. It also sets of chemical changes in the joint that the body’s natural reparative process can’t keep up with. Cartilage cells begin to die and telomeres – regions at the end of chromosomes involved in their replication and stability – shorten.

For as many as 50 percent of people who suffer cartilage injuries, the result is osteoarthritis, which may begin as soon as three months after a severe injury or decades after a minor one, says Joseph A. Buckwalter, MD, professor and chair of the Department of Orthopaedic Surgery at the University of Iowa Hospitals and Clinics in Iowa City, Iowa.

The risk of OA development following injury is influenced by the type of injury as well as an individual’s characteristics, such as age, sex and body mass index.

Findings Could Lead to New Therapies

While there are currently no therapies to stop OA or its progression, research into these factors could eventually lead to new ways to treat – or even prevent – OA and to target preventive efforts and therapeutics to people at greatest risk.

For example, an understanding of the chemical changes that occur in the joint following injuries could lead to therapies to interfere with those changes. Dr. Buckwalter and his team are targeting some of the molecular causes of cartilage loss. Their studies are moving into animal models.

Findings about leptin’s role in OA suggest that maintaining a healthy weight may help OA in more ways beyond reducing mechanical stress and that a low-fat diet – or therapies to interfere with leptin – could eventually prove useful for managing the disease, says Guilak. “If we know that some inflammatory mediator, whether it is leptin or something downstream of leptin, causes the joint damage, we could potentially take this one step further and interfere with that process,” he says.

Genetic findings could have multiple implications as well. “We hope that by learning about gene mutations we will eventually be able to define a therapeutic approach to these diseases, either by manipulating the gene itself or by downstream manipulation to modify the effects of the mutation,” says Dr. Moskowitz.