Research shows bone loss causes joint pain from alphaviral diseases

April 15, 2014 by Marcia Malory report
Osteoblasts actively synthesizing osteoid. Credit: Robert M. Hunt; Wikipedia.

(Medical Xpress)—Arthritogenic alphaviruses such as Ross River virus (RRV) cause disabling joint pain. To understand what causes this pain, Suresh Mahalingam of Griffith University in Australia and his team studied how RRV affects human and mouse osteoblasts. They found that RRV concentrates in osteoblasts, where it induces the production of inflammatory cytokines. This leads to increased bone loss, which causes pain. The research appears in the Proceedings of the National Academy of Sciences.

RRV, sindbis (SINV) and chikungunya virus (CHIKV) belong to a group of alphaviruses that cause pain resembling the pain of rheumatoid arthritis. This pain can last for months after the viruses themselves are gone. Usually, doctors tell patients who have contracted arthritis-inducing alphaviruses to manage their pain by taking anti-inflammatory drugs like ibuprofen.

Recent research shows that patients with CHIKV develop in their joints. Mahalingam and his colleagues wanted to see whether alphaviruses cause . They studied the effect of RRV on osteoblasts, cells involved in bone synthesis.

First, the researchers infected cultured human osteoblasts with RRV. This stimulated the production of the cytokines IL-6, CCL2 and IL-1β, which promote bone loss. The RRV-infected osteoblasts had higher RANKL levels and lower OPG levels than non-infected osteoblasts. An elevated RANKL/OPG ratio disturbs bone homeostasis, causing excessive loss of bone. When Mahalingam's team examined the synovial fluid of patients with RRV, they found these patients also had high RANKL/OPG ratios.

The researchers then studied RRV-infected mice. After killing the mice, they examined the leg and foot bones. They found that most of the virus was concentrated in osteoblasts, rather than in the marrow, reticulocytes or leukocytes. The virus remained in the osteoblasts for 21 days post infection, while it disappeared from the other parts of the bone after two days.

Microcomputed tomography of bones from RRV-infected mice showed clear evidence of bone loss in the vertebrae and tibial ephiphysis by the 15th day. When the team examined osteoblasts cultured from mice with RRV, they found that, as with cultured human , RRV induced production of IL-6, CCL2 and IL-1β.

Mahalingam's team then tested whether an antibody that neutralizes IL-6 could prevent bone loss from RRV infection. They treated the hind limbs of RRV-infected mice with an IL-6 neutralizing antibody 10 days post infection, and found that the ratio of bone volume to tissue volume was preserved.

The research shows that IL-6 plays an important role in causing bone loss and the subsequent associated with arthritis-inducing alphaviruses like RRV. It suggests that would benefit by taking cytokine-inhibiting antibodies in the early stages of these diseases.

Explore further: Choloroquine reduces formation of bone resorbing cells in murine osteoporosis

More information: Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss, Weiqiang Chen, PNAS, DOI: 10.1073/pnas.1318859111

Abstract
Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. The ability of alphaviruses to induce bone pathologies remains poorly defined. Here we show that primary human osteoblasts (hOBs) can be productively infected by RRV. RRV-infected hOBs produced high levels of inflammatory cytokine including IL-6. The RANKL/OPG ratio was disrupted in the synovial fluid of RRV patients, and this was accompanied by an increase in serum Tartrate-resistant acid phosphatase 5b (TRAP5b) levels. Infection of bone cells with RRV was validated using an established RRV murine model. In wild-type mice, infectious virus was detected in the femur, tibia, patella, and foot, together with reduced bone volume in the tibial epiphysis and vertebrae detected by microcomputed tomographic (µCT) analysis. The RANKL/OPG ratio was also disrupted in mice infected with RRV; both this effect and the bone loss were blocked by treatment with an IL-6 neutralizing antibody. Collectively, these findings provide previously unidentified evidence that alphavirus infection induces bone loss and that OBs are capable of producing proinflammatory mediators during alphavirus-induced arthralgia. The perturbed RANKL/OPG ratio in RRV-infected OBs may therefore contribute to bone loss in alphavirus infection.

Related Stories

Choloroquine reduces formation of bone resorbing cells in murine osteoporosis

December 9, 2013
Bone homeostasis requires precise balance between deposition of new bone by osteoblasts and resorption of old bone by osteoclasts. Bone diseases, including osteoporosis and rheumatoid arthritis, are the result of increased ...

Researchers reverse bone loss in immune disorder

March 26, 2014
Patients with leukocyte adhesion deficiency, or LAD, suffer from frequent bacterial infections, including the severe gum disease known as periodontitis. These patients often lose their teeth early in life.

Researchers identify risks for death from H7N9 avian flu virus

December 24, 2013
(Medical Xpress)—Since March 2013, the avian flu virus H7N9 has infected 134 people and caused 44 deaths. Among those infected, many, but not all, patients develop severe symptoms, including pneumonia and acute respiratory ...

Research uncovers new protein to treat damaged bones

January 10, 2013
Korean researchers believe that the 'DJ-1 protein' can be used to promote the formation of new bone tissue in patients suffering from osteoporosis by improving communication between bone making cells (osteoblasts) and blood ...

Mouse study suggests vitamin E may weaken bones

March 4, 2012
(HealthDay) -- Vitamin E may stimulate cells that result in bone loss, a new study suggests.

Recommended for you

Post-stroke patients reach terra firma with new exosuit technology

July 26, 2017
Upright walking on two legs is a defining trait in humans, enabling them to move very efficiently throughout their environment. This can all change in the blink of an eye when a stroke occurs. In about 80% of patients post-stroke, ...

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.