Osteoclast differentiation alters monocyte inflammatory responses to Staphylococcus aureus

Abstract

Abstract Staphylococcus aureus is the major causative agent of bacterial osteomyelitis, an invasive infection of bone. Osteomyelitis is associated with significant bone destruction, bone-resorbing osteoclasts have been implicated in this process. Osteoclasts differentiate from monocyte precursors in response to the canonical osteoclastogenic cytokine RANKL, or receptor activator of (NF)-κB ligand. The process of osteoclastogenesis involves significant transcriptional reprogramming, thereby altering inflammatory responses of osteoclasts, relative to inflammatory monocytes or macrophages. In this study, we sought to elucidate mechanisms of infection-associated bone loss by defining how RANKL shapes osteoclast responses to S. aureus secreted virulence factors and pathogen-associated molecular patterns. We found that, whereas RANKL-naïve monocytes produce significant amounts of IL-1β in response to priming with S. aureus supernatants, differentiated osteoclasts do not. Osteoclasts instead undergo enhanced caspase-dependent cell death, relative to RANKL-naïve monocytes, without associated IL-1β release. This cell death occurs in response to virulence factors regulated by the S. aureus accessory gene regulator (Agr) quorum-sensing system. These results suggest that RANKL alters monocyte-lineage inflammatory responses to microbial pathogens, that osteoclasts have enhanced susceptibility to S. aureus cytotoxins. In parallel studies, we also found that S. aureus supernatants promote osteoclast differentiation of RANKL-primed monocytes in a TLR-dependent manner. Collectively, these studies contribute to the mechanistic understanding of dysregulated bone homeostasis and bone loss during infection. Supported by R01AI161022, R01AI145992, R01AI132560, Burroughs Wellcome Fund and T32AR059039.