Toll-Like Receptor 2 Stimulation on Osteoblasts Mediates Staphylococcus aureus-Induced Bone Resorption and Osteoclastogenesis through Enhanced RANKL
(English)Manuscript (preprint) (Other academic)
Severe Staphylococcus aureus (S. aureus) infections pose an immense threat to population health and constitute a great burden for the health care worldwide. Inter alia, S. aureus septic arthritis is a disease with high mortality and morbidity caused by destruction of the infected joints and systemic bone loss, osteoporosis. Toll-Like receptors (TLRs) are innate immune cell receptors recognizing a variety of microbial molecules and structures. S. aureus recognition via TLR2 initiates a signaling cascade resulting in production of various cytokines, but the mechanisms by which S. aureus causes rapid and excessive bone loss are still unclear. Therefore, we investigated how S. aureus regulates periosteal/endosteal osteoclast formation and bone resorption.
S. aureus stimulation of neonatal mouse parietal bone induced ex vivo bone resorption and osteoclastic gene expression. This effect was associated with increased mRNA and protein expression of receptor activator of NF-kB ligand (RANKL) without significant change in osteoprotegerin (OPG) expression. S. aureus also increased the expression of proinflammatory cytokines and prostaglandins in parietal bones but the stimulatory effect of S. aureus on bone resorption and Tnfsf11 mRNA expression was independent of these cytokines and prostaglandins. Stimulation of isolated periosteal osteoblasts with S. aureus also resulted in increased expression of Tnfsf11 mRNA, an effect lost in osteoblasts from Tlr2 knockout mice. S. aureus stimulated osteoclastogenesis in isolated periosteal cells without affecting RANKL-stimulated resorption. In contrast, S. aureus inhibited RANKL-induced osteoclast formation in bone marrow macrophages. These data show that S. aureus enhances bone resorption and periosteal osteoclast formation by increasing osteoblast RANKL production through TLR2. In contrast, S. aureus inhibits osteoclastogenesis from bone marrow derived precursors. Our study indicates the importance of using different in vitro approaches for studies of regulation of osteoclastogenesis by S. aureus to obtain better understanding of the complex mechanisms of S. aureus bone destruction in vivo.
IdentifiersURN: urn:nbn:se:umu:diva-110287OAI: oai:DiVA.org:umu-110287DiVA: diva2:861975