Even though one in five people develops osteoarthritis (OA), little is known about what causes the disease. However, because the condition is so common, researchers have always suspected a genetic link. Family and twin studies show that osteoarthritis can be inherited. But researchers scanning genomes (every gene in the body) looking for changes that may increase risk of OA don’t have a straightforward path.

“Osteoarthritis is probably a multi-gene disease and there’s likely an interaction between the environment and genetic susceptibility,” says Joanne Jordan, MD, an arthritis researcher and chief of Rheumatology, Allergy, and Immunology at the University of North Carolina in Chapel Hill.

Studying many aspects of genetics may help researchers identify people who are at higher risk of developing OA, such as those whose risk factors include family history of OA, hormonal changes, injury or obesity.

Although such complexity makes studying the genetics of OA very difficult, over the past decade or so, OA researchers have taken advantage of an abundance of improving technologies to pinpoint small genetic variations (called alleles) that may increase the risk of osteoarthritis. One technique allows researchers to study the genome of large populations of research participants. In another effort, scientists examining the disease on a molecular level use sensitive new assays to detect changes in chromosomes that may herald early changes that eventually progress to OA’s hallmark cartilage damage.

Two recent studies show the power of these technologies to spot people who may harbor the genetic underpinnings of OA. The goal of these studies is to detect OA at an early stage and then to find new treatments before the joints reach end-stage disease for which the only treatment is total joint replacement.

Just as our bodies don’t work as well as we age, cells get sluggish with aging, too. Like other aging cells, the cells that produce and maintain cartilage, called chondrocytes, go into a kind of sleep, or senescence. Once chondrocytes reach this slumber, they can’t perform the tasks necessary to keep cartilage healthy, such as responding to growth factors and switching certain genes on or off. Without the right genes working in unison, cartilage breaks down and can’t be repaired, says Jean-Marie Delaissé, PhD, Head of Research in the Clinical Research Unit at Vejle Hospital in Denmark.
 

Recently, Delaissé and his colleagues looked for a link between senescent chondrocytes and cartilage damage. Cells in this sleep-like state have been linked to a chromosomal change in which telomeres (pronounced TEAL-oh-meres), which form caps at the ends of chromosomes, like the hard tips on shoelaces, become shortened. Telomere shortening occurs as cells divide over and over again, or as cells are submitted to stress.

Researchers have already shown that very short telomeres can push cells into senescence. Delaissé wanted to find out whether chondrocytes with short telomeres were linked to cartilage damage. His team used a new assay (laboratory test) that can detect shortening of individual telomeres – previous assays could only detect average telomeres length – but a few recent studies have shown that only a few shortened temeres (and perhaps even one shortened telomere) can push cells into senescence.  With that in mind, Delaissé’s team used cartilage tissue left over from knee replacement surgery and studied cartilage in four different places, from the worst cartilage lesion to farthest away.

The results, published in January 2012 in Arthritis Research & Therapy, showed that telomeres closest to the most damaged cartilage tissue were shortest in length, perhaps indicating that stress from damaged tissue prevents cartilage repair.  

“We hope to extend this research to more patients and to other joints,” says Delaisse. “Targeting telomere shortening may help us produce a therapy that prevents articular cartilage [the cartilage in joints] from breaking down.”

Another way to study genetic changes that may lead to OA is to screen a large number of people to uncover any genes – even those not previously suspected – that might harbor such changes. A team of researchers in the United Kingdom published a study in the American Journal of Human Genetics in September 2011, using a systemic method to screen a large group of people with hip or knee OA. They compared 3,177 people who needed total joint replacement to 4,894 people who probably did not have osteoarthritis. The search uncovered a variation in a gene called MCF2L, which directs nerve growth.
 

“For every copy of the risk allele carried, individuals are 17 percent more likely to develop OA compared to those who do not carry the risk allele,” lead author Eleftheria Zeggini PhD, of the Wellcome Trust Sanger Institute in the UK, says.

Before any genetic test could be developed to detect individual risk, researchers need to figure out how MCF2L works to increase OA risk. In their next series of studies, Zeggini and her team will conduct these functional studies as well as continue to investigate the genetic causes of OA and related traits.

“This particular study was very elegantly performed to a very high standard, which gave them the ability to find links on a finer level that would have been in prior days not able to be seen,” says Dr. Jordan.

The fact that some participants in the study’s control group may have had very early OA reinforces the importance of the result, Dr. Jordan adds, because if so, it should be harder for researchers to find a genetic signal for OA and the signal was indeed present. One limitation of the study is the fact that the subjects all came from European populations; the results may or may not hold for people elsewhere.

The MCF2L gene is the third in which researchers have found an allele that raises the risk of arthritis.

Because MCF2L directs nerve growth factor, it may be related to pain and OA, says Dr. Jordan. A clinical trial that tested a drug that targeted nerve growth factor helped with pain, but some people quickly progressed to OA and the trial was stopped early.

 “If there’s a certain genotype that we can bring to the clinic one day that would identify these individuals, then we can help with prevention and early intervention, once we have that information,” says Dr. Jordan. “The day will come.”