BACTERIAL PORINS STIMULATE BONE-RESORPTION

Porins are abundant outer membrane proteins of gram-negative bacteria involved in transport of low-molecular-mass molecules, During the past decade, porins from a number of bacteria have also been shown to have proinflammatory activities including inducing the synthesis of proinf lammatory mediators (cytokines, platelet-activating factor, and nitric oxide) in cultured cells and inducing inflammation in vivo. With this range of actions, it was possible that porins could also interact wit h bone cells to cause aberrant bone remodeling and that this could con tribute to the bone destruction seen in gram-negative bone infections, By using purified preparations of Salmonella typhimurium and Pseudomo nas aeruginosa porins, in the presence of polymyxin B, it was possible to induce concentration-dependent loss of calcium from cultured murin e calvaria at porin concentrations in the range of 1 to 10 nM. The mec hanism of action of the porins was determined by the inclusion of inhi bitors of cyclooxygenase or inflammatory cytokines in the culture medi a, The bone-resorbing activity of both porins was not inhibited by the cyclooxygenase inhibitor indomethacin or by neutralizing the activity of tumor necrosis factor, Indeed, relatively high concentrations of t hese agents produced an unexpected increase in the bone resorption ind uced by the porins, In contrast, porin-induced bone resorption could b e inhibited by relatively high concentrations of the natural inhibitor of interleukin-l (IL-1 receptor antagonist), It appears that these po rins stimulate bone resorption by a mechanism distinct from that of li popolysaccharide, and the possibility therefore exists that porins pla y a role in bone destruction in gram-negative bacterial infections of bone.