Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2014

Arthritogenic alphaviral infection perturb osteoblasts function and triggers pathologic bone loss (#28)

Weiqiang Chen 1 , Suan Sin Foo 1 , Nestor E Rulli 1 , Adam Taylor 1 , Kuo-Ching Sheng 1 , Lara J Herrero 1 , Belinda L Herring 1 , Brett A Lidbury 2 , Rachel W Li 2 , Nicole C Walsh 3 , Natalie A Sims 3 , Paul N Smith 4 , Suresh Mahalingam 1
  1. Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
  2. The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
  3. St. Vincent's Institute, The University of Melbourne, Fitzroy, VIC, Australia
  4. The Canberra Hospital, Canberra, ACT, Australia

Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus (SINV) and chikungunya virus (CHIKV) are associated with outbreaks of polyarthritis. In the bone remodelling system, a coordinated action of bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts is required to maintain bone homeostasis. Osteoclastogenesis is regulated by OB through key factors such as receptor activator of nuclear factor-κβ ligand (RANKL) and osteoprotegerin (OPG), a soluble decoy receptor for RANKL. An increase of the RANKL/OPG ratio leads to excessive OC activity and may result in osteolytic pathologies. The ability of alphaviruses to induce osteoclastic bone resorption remains undefined. The RANKL/OPG ratio was disrupted in RRV patients and accompanied by an increase in serum TRAP5b levels. Primary human osteoblasts (hOBs) were isolated from trabecular bone fragments and infected with RRV and the effects of infection in hOBs were determined by flow cytometry, plaque assays, ELISAs, and real-time PCR. Primary hOBs were susceptible to RRV infection and supported the production of infectious virus.1  In response to RRV infection, the primary hOBs produced higher levels of inflammatory cytokines, including IL-6, IL-1β and CCL2, together with an increase osteoclastogenesis. The architecture and virus localization in bones of RRV-infected C57BL/6 wild-type (WT) mice was determined using micro-computed tomographic (µCT) analysis and immunohistochemistry. In RRV-infected mice, virus was detected in the femur, tibia, patella and foot tissues, together with reduced bone volume in the tibial epiphysis and vertebrae detected. With the neutralization of IL-6 in RRV-infected mice, the effects of RRV-induced bone loss was ameliorated. These findings provide the first evidence that OBs are capable of producing pro-inflammatory mediators in alphavirus-induced arthritis and perturbing the RANKL/OPG ratio of RRV-infected OB, which contribute to the pathogenic bone loss in an alphavirus infection.

  1. Chen W, et al. (2014) Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss. Proc Natl Acad Sci U S A: In press.
  2. Foo SS*, Chen W*, et al. (2011) The genetics of alphaviruses. Future Virology 6: 1407-1422. (*Joint first authors)