Deciphering the cause of viral joint pain

May 07, 2014 09:47 pm | Updated 09:47 pm IST

The chikungunya virus often leaves those it infects with severe joint pains. This could be the result of arthritic changes brought about by the virus getting into certain cells in the bone, suggests research that was recently published.

Suresh Mahalingam at the Griffith University in Australia and colleagues studied such changes using a closely related virus, the Ross River virus (RRV). This virus infected bone-forming cells, known as osteoblasts. The infected cells began secreting molecules that attracted certain immune cells (monocytes) and turned them into bone-devouring cells called osteoclasts. These osteoclasts produced arthritic bone loss, they reported in a paper in the Proceedings of the National Academy of Sciences .

The work, along with other recent studies, suggested that infection by RRV and related viruses “may directly lead to arthritis” and could be amenable to forms of treatment for that ailment, write Kate D. Ryman and William B. Klimstra of the University of Pittsburgh in the U.S. in a commentary on the paper published in the same journal.

The authors showed that when the RRV infected human osteoblasts grown in culture, those cells began to produce various molecules, including some that served to bring monocytes to infected bone sites

The infected osteoblasts also began churning out interleukin-6 (IL-6), a molecule that induced those same cells to produce more of a protein, RANKL (receptor activator of nuclear factor-kappaB ligand). The binding of RANKL to a molecule on the surface of monocytes, which had been attracted to the infection sites, coaxed them to turn into osteoclasts, the cells that can break down bone.

Such differentiation into osteoclasts could be held in check by yet another molecule secreted by osteoblasts, osteoprotegerin (OPG), which locks on to the RANKL. However, IL-6 not only causes osteoblasts to ramp up RANKL secretion but reduces the amount of OPG they put out. This “disruption of the RANKL/OPG system can tilt the balance toward bone resorption,” noted Prof. Mahalingam and colleagues in their PNAS paper.

They found that the fluid drawn from the joints of RRV patients had elevated levels of the protein and lowered amounts of OPG. These patients also had higher levels of a protein marking the formation of osteoclasts. A previously published study carried out by a different group has shown that the chikungunya virus too could infect osteoblasts, leading those cells to secrete more IL-6 and RANKL as well as less OPG.

The scientists infected laboratory mice with RRV, and found that the virus could be detected in osteoblasts embedded in a membrane that surrounds bones. By about two weeks after infection, the mice showed “clear bone loss” at several places. They gave some infected mice an antibody that blocked IL-6, a technique similar to an antibody treatment for rheumatoid arthritis that is currently going through clinical trials. The mice that received the antibodies not only showed greatly reduced bone loss, but their RANKL-OPG levels also improved.

The work demonstrated that “IL-6 is a critical mediator of the RRV-induced increase in RANKL/OPG ratio and bone loss,” the scientists said in their PNAS paper.

Many chikungunya patients suffer chronic joint pains that lasted for months and sometimes years, observed Prof. Mahalingam in an email. “What contributes to this is not known. Our findings suggest that virus-induced bone loss might be responsible. Our findings also suggest that using existing drugs that target factors that trigger bone loss might be useful in treating patients.”

It is important to determine whether chikungunya and other viruses closely related to RRV also produced similar responses in laboratory animals as well as in humans, said Dr. Ryman and Dr. Klimstra in their commentary. The study may also shed light on the arthritis produced by a wide range of other viruses, including the one that causes dengue.

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