Substance P Exacerbates the Inflammatory and Pro-osteoclastogenic Responses of Murine Osteoclasts and Osteoblasts to Staphylococcus aureus

Staphylococcus aureus infections of bone tissue are associated with inflammatory bone loss. Resident bone cells, including osteoblasts and osteoclasts, can perceive S. aureus and produce an array of inflammatory and pro-osteoclastogenic mediators, thereby contributing to such damage. The neuropeptide substance P (SP) has been shown to exacerbate microbially induced inflammation at sites such as the gut and the brain and has previously been shown to affect bone cell differentiation and activity. Here we demonstrate that the interaction of SP with its high affinity receptor, neurokinin-1 receptor (NK-1R), expressed on murine osteoblasts and osteoclasts, augments the inflammatory responses of these cells to S. aureus challenge. Additionally, SP alters the production of pro- and anti-osteoclastogenic factors by bacterially challenged bone cells and their proteolytic functions in a manner that would be anticipated to exacerbate inflammatory bone loss at sites of infection. Furthermore, we have demonstrated that the clinically approved NK-1R antagonist, aprepitant, attenuates local inflammatory and pro-osteoclastogenic mediator expression in an in vivo mouse model of post-traumatic staphylococcal osteomyelitis. Taken together, these results indicate that SP/NK-1R interactions could play a significant role in the initiation and/or progression of damaging inflammation in S. aureus bone infections and suggest that the repurposing of currently approved NK-1R antagonists might represent a promising new adjunct therapy for such conditions.