Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss

Weiqiang Chen, Suan Sin Foo, Nestor E. Rulli, Adam Taylor, Kuo Ching Sheng, Lara J. Herrero, Belinda L. Herring, Brett A. Lidbury, Rachel W. Li, Nicole C. Walsh, Natalie A. Sims, Paul N. Smith, Suresh Mahalingam*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    92 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)6040-6045
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume111
    Issue number16
    DOIs
    Publication statusPublished - 22 Apr 2014

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