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Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss

Significance Persistent polyarthritis, which occurs in 30–40% of alphavirus-infected patients, has been proposed to be caused by proinflammatory mediators such as IL-6. In the present study we investigated the susceptibility and response of primary human osteoblasts to Ross River virus (RRV) infection and determined whether infection could result in bone pathology. RRV infection of osteoblasts resulted in increased receptor activator of nuclear factor-kappaB ligand (RANKL) but decreased osteoprotegerin (OPG). We are the first to report that alphavirus infection results in bone loss in an established RRV murine model and that this bone loss is prevented by IL-6 inhibition. These findings reveal that RRV can disrupt bone homeostasis and that osteoblasts play an important role in alphavirus-induced arthritis by regulating IL-6 and contribute to bone loss by disrupting the RANKL/OPG balance. 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.