Substance P exacerbation of staphylococcal bone damage

Project Summary
Bone disorders such as osteomyelitis that result from bacterial infection are associated
with severe inflammation and progressive bone loss. Staphylococcus aureus is the most
common causative agent of osteomyelitis and the incidence and severity of
staphylococcal osteomyelitis appears to be increasing despite improvements in
prophylaxis and diagnosis. Dysregulation of osteoclast formation and activity results in
bone destruction and/or abnormal bone remodeling at sites of infection, and osteoblasts
play an essential role in the regulation of these bone-resorbing cells. In addition,
bacterially infected osteoblasts and osteoclasts are capable of producing an array of
immune mediators that could promote the recruitment and activation of inflammatory
leukocytes in bone tissue. The neuropeptide substance P (SP) is increasingly
recognized to exacerbate inflammation in a range of tissues including the gut, skin, and
central nervous system. Given the extensive innervation of bone tissue with SP-
containing nerve fibers, the functional expression of the specific receptor for SP (NK-1R)
by bone cells, and previous evidence that this neuropeptide can modulate bone cell
responses, we suggest that SP/NK-1R interactions exacerbate inflammation in
osteomyelitis. In this application, we propose a comprehensive preclinical evaluation of
the ability of this neuropeptide to augment inflammation in isolated murine and human
resident bone cells and an established in vivo animal model of staphylococcal
osteomyelitis. This work builds upon our prior work and will test the hypothesis that
inhibition of SP/NK-1R interactions attenuates the immune and osteolytic responses of
resident bone cells to bacteria. Furthermore, these studies represent an essential step
in evaluating the therapeutic potential of repurposing clinically approved NK-1R
antagonists as an adjunctive therapy to limit staphylococcal osteomyelitis-associated
inflammatory bone loss and/or abnormal bone remodeling, and may point to neurogenic
input as a therapeutic target for the treatment of inflammatory bone disorders in general.