osteoprotegerin and Streptococcal-Infections

Human CD46 is a receptor for the M protein of group A streptococcus (GAS). The emm1 GAS strain GAS472 was isolated from a patient suffering from streptococcal toxic shock-like syndrome. Human CD46-expressing transgenic (Tg) mice developed necrotizing fasciitis associated with osteoclast-mediated progressive and severe bone destruction in the hind paws 3 days after subcutaneous infection with 5 × 10(5) colony-forming units of GAS472. GAS472 infection induced expression of the receptor activator of nuclear factor-κB ligand (RANKL) while concomitantly reducing osteoprotegerin expression in the hind limb bones of CD46 Tg mice. Micro-computed tomography analysis of the bones suggested that GAS472 infection induced local bone erosion and systemic bone loss in CD46 Tg mice. Because treatment with monoclonal antibodies (mAbs) against mouse CD4(+) and CD8(+) T lymphocytes did not inhibit osteoclastogenesis, T lymphocyte-derived RANKL was not considered a major contributor to massive bone loss during GAS472 infection. However, immunohistochemical analysis of the hind limb bones showed that GAS472 infection stimulated RANKL production in various bone marrow cells, including fibroblast-like cells. Treatment with a mAb against mouse RANKL significantly inhibited osteoclast formation and bone resorption. These data suggest that increased expression of RANKL in heterogeneous bone marrow cells provoked bone destruction during GAS infection.

Topics: Animals; Bone Resorption; Gene Expression; Hindlimb; Humans; Male; Membrane Cofactor Protein; Mice, Inbred C57BL; Mice, Transgenic; Osteocytes; Osteoprotegerin; RANK Ligand; Streptococcal Infections; Streptococcus pyogenes; Tibia; Transcriptional Activation

Bacterial arthritis is a rapidly progressive and highly destructive joint disease in humans, with Staphylococcus aureus and Neisseria gonorrhoeae the major causative agents, although beta-hemolytic streptococci as well often induce the disease. We demonstrate here that intravenous inoculation of CD-1 mice with the group A streptococcus (GAS) species Streptococcus pyogenes resulted in a high incidence of septic arthritis. Signs of arthritis emerged within the first few days after injection, and bacterial examinations revealed that colonization of the inoculated GAS in the arthritic joints persisted for 21 days. Induction of persistent septic arthritis was dependent on the number of microorganisms inoculated. Immunohistochemical staining of GAS with anti-GAS antibodies revealed colonization in the joints of infected mice. Cytokine levels were quantified in the joints and sera of infected mice by using an enzyme-linked immunosorbent assay. High levels of interleukin-1beta (IL-1beta) and IL-6 were detected in the joints from 3 to 20 days after infection. We noted that an increase in the amount of receptor activator of NF-kappaB ligand (RANKL), which is a key cytokine in osteoclastogenesis, was also evident in the joints of the infected mice. RANKL was not detected in sera, indicating local production of RANKL in the infected joints. Blocking of RANKL by osteoprotegerin, a decoy receptor of RANKL, prevented bone destruction in the infected joints. These results suggest that GAS can colonize in the joints and induce bacterial arthritis. Local RANKL production in the infected joints may be involved in bone destruction.

Topics: Animals; Arthritis, Infectious; Bone Resorption; Carrier Proteins; Colony Count, Microbial; Disease Models, Animal; Female; Glycoproteins; Humans; Interleukin-1; Interleukin-6; Membrane Glycoproteins; Mice; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Streptococcal Infections; Streptococcus pyogenes; Time Factors