Brucella and Osteoarticular Cell Activation: Partners in Crime

Abstract

Osteoarticular brucellosis is the most common presentation of human active disease although its prevalence varies widely. The three most common forms of osteoarticular involvement are sacroiliitis, spondylitis, and peripheral arthritis. The molecular mechanisms implicated in bone damage have been recently elucidated. B. abortus induces bone damage through diverse mechanisms in which TNF-α and the receptor activator of nuclear factor kappa-B ligand (RANKL)-the natural modulator of bone homeostasis are involved. These processes are driven by inflammatory cells, like monocytes/macrophages, neutrophils, Th17 CD4⁺ T, and B cells. In addition, Brucella abortus has a direct effect on osteoarticular cells and tilts homeostatic bone remodeling. These bacteria inhibit bone matrix deposition by osteoblasts (the only bone cells involved in bone deposition), and modify the phenotype of these cells to produce matrix metalloproteinases (MMPs) and cytokine secretion, contributing to bone matrix degradation. B. abortus also affects osteoclasts (cells naturally involved in bone resorption) by inducing an increase in osteoclastogenesis and osteoclast activation; thus, increasing mineral and organic bone matrix resorption, contributing to bone damage. Given that the pathology induced by Brucella species involved joint tissue, experiments conducted on synoviocytes revealed that besides inducing the activation of these cells to secrete chemokines, proinflammatory cytokines and MMPS, the infection also inhibits synoviocyte apoptosis. Brucella is an intracellular bacterium that replicates preferentially in the endoplasmic reticulum of macrophages. The analysis of B. abortus-infected synoviocytes indicated that bacteria also replicate in their reticulum suggesting that they could use this cell type for intracellular replication during the osteoarticular localization of the disease. Finally, the molecular mechanisms of osteoarticular brucellosis discovered recently shed light on how the interaction between B. abortus and immune and osteoarticular cells may play an important role in producing damage in joint and bone.

Keywords: B and T cells and Brucella; osteoarticular brucellosis; osteoblast; osteoclastogenesis; synoviocyte.

FIGURE 1

Bone damage induced by soluble mediators secreted by resident and infiltrating cells upon infection with Brucella abortus. OSTEOBLAST: B. abortus infection of osteoblast induces RANKL, MMP-2, GM-CSF, and chemokines (IL-8 and MCP-1) expression; induces apoptosis, and inhibits osteoblast differentiation. Chemokines attract monocytes and neutrophils to the site of infection, and these cells secrete MMP-9. TNF-α secreted by B. abortus-infected monocytes inhibits differentiation and induces apoptosis and RANKL expression in osteoblasts. It is the main cytokine involved in the secretion of MMP-9 by monocytes. OSTEOCYTE: B. abortus infection induces MMP-2, RANKL proinflamatory cytokines, and KC secretion by osteocytes. TNF-α and RANKL from B. abortus-infected osteocytes induce osteoclastogenesis. B. abortus infection inhibits the expression of Cx43, but does not modify integrins expression. In contrast, supernatants from B. abortus infected macrophages inhibit Cx43 and integrins inducing osteocyte apoptosis. SYNOVIAL FIBROBLAST: B. abortus infection induces MMP-2 and RANKL expression, and inhibits synoviocyte apoptosis through the upregulation of anti-apoptotic factors (cIAP-2, clusterin, livin, and P21/CIP/CDNK1A) and the reduction in the expression of proteins involved in apoptosis (P-p53(S15) and TNFRI/TNFRSF1A). IMMUNE CELLS AND OSTEOARTICULAR BRUCELLOSIS. Supernatants from B. abortus-infected macrophages induce osteoclastogenesis via TNF-α induction. T cells secrete IL-17 in response to supernatants from B. abortus-infected macrophages, which induce osteoclastogenesis via TNF-α secreted by osteoclast precursors. B. abortus-infected B cells secrete RANKL that induce osteoclastogenesis. L-OMP19. Brucella lipoproteins mimic responses mediated by B. abortus infection in neutrophils, monocytes and synovial fibroblasts and these responses require TLR2.