Streptococcus pyogenesInfection Induces Septic Arthritis with Increased Production of the Receptor Activator of the NF-κB Ligand

Abstract

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-1␤ (IL-1␤) 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-B 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.

CD46 Contributes to the Severity of Group A Streptococcal Infection

“…The capacity of S. pyogenes to cause arthritis as well as lethal disease has been studied in mouse model systems using i.v. inoculation doses of 2 ϫ 10 8 to 4 ϫ 10 8 cells per mouse (40). To study the in vivo impact of CD46, we challenged CD46 transgenic mice and nontransgenic mice with 3 ϫ 10 8 S. pyogenes cells i.v.…”

Changes in the Novel Orphan, C5a Receptor (C5L2), during Experimental Sepsis and Sepsis in Humans

“…Several studies support the concept that decoy receptors are beneficial during inflammatory responses. In a model of Streptococcus pyogenes-induced arthritis in mice, the presence of osteoprotegerin, a decoy receptor for receptor activator of NF-B ligand, prevented bone destruction in the infected joints (41). In another inflammation model in which Fas ligand-induced lung inflammatory injury was studied, the presence of the decoy receptor 3 analog reduced PMN recruitment into the alveolar compartment and inhibited the appearance in bronchoalveolar lavage fluids of proinflammatory chemokines (42).…”

The Cytolethal Distending Toxin Induces Receptor Activator of NF-κB Ligand Expression in Human Gingival Fibroblasts and Periodontal Ligament Cells

“…The role of the RANKL-RANK-OPG system in inflammation-induced bone loss is demonstrated by the observation that OPG treatment decreases local bone loss in experimentally induced periodontitis and arthritis (23,43,46,55,59). In inflammation-induced local bone resorption, it has been suggested that RANKL is expressed by resident osteoblasts, stimulated by proinflammatory cytokines, such as interleukin-1, tumor necrosis factor alpha, or cytokines of the interleukin-6 family (5,26).…”