Apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis

Abstract

The mechanisms underlying the destruction of bone tissue in osteomyelitis are only now being elucidated. While some of the tissue damage associated with osteomyelitis likely results from the direct actions of bacteria and infiltrating leukocytes, perhaps exacerbated by bacterial manipulation of leukocyte survival pathways, infection-induced bone loss predominantly results from an uncoupling of the activities of osteoblasts and osteoclasts. Bacteria or their products can directly increase osteoclast formation and activity, and the inflammatory milieu at sites of infection can further promote bone resorption. In addition, osteoclast activity is critically regulated by osteoblasts that can respond to bacterial pathogens and foster both inflammation and osteoclastogenesis. Importantly, bone loss during osteomyelitis is also brought about by a decline in new bone deposition due to decreased bone matrix synthesis and by increased rates of osteoblast apoptosis. Extracellular bacterial components may be sufficient to reduce osteoblast viability, but the causative agents of osteomyelitis are also capable of inducing continuous apoptosis of these cells by activating intrinsic and extrinsic cell death pathways to further uncouple bone formation and resorption. Interestingly, bacterial internalization appears to be required for maximal osteoblast apoptosis, and cytosolic inflammasome activation may act in concert with autocrine/paracrine death receptor-ligand signaling to induce cell death. The manipulation of apoptotic pathways in infected bone cells could be an attractive new means to limit inflammatory damage in osteomyelitis. However, the mechanism that is the most important in bacterium-induced bone loss has not yet been identified. Furthermore, it remains to be determined whether the host would be best served by preventing osteoblast cell death or by promoting apoptosis in infected cells.

Keywords: apoptosis; bacterial infection; inflammation; osteoblasts; osteoclasts; osteoimmunology; osteomyelitis.

Figure 1

Bacterial infection leads to inflammatory bone loss resulting from increased formation and/or activity of bone resorbing osteoclasts, and a decrease in the number of bone forming osteoblasts. Osteoblasts (OB) can recognize bacteria and their components such as LPS, flagellin, or unmethylated CpG DNA motifs (CpG) via cell surface pattern recognition receptors including TLRs 4, 5, and 9, and the cytosolic sensors NOD1, NOD2, and NLRP3. These microbial sensors can directly or indirectly (via PGE2 autocrine/paracrine signaling) induce the rapid release of chemokines such as CCL2, CCL3, and CXCL10 to recruit leukocytes including T-lymphocytes (T) to the site of infection. Bacterially stimulated osteoblasts show elevated levels of these bacterial sensors and can also express cell surface molecules including MHC class II and CD40 that can elicit antigen-specific activation of infiltrating T-cells. Bacteria and their components can directly induce the formation and activity of osteoclasts (OC) or indirectly activate these cells via the autocrine/paracrine actions of released TNF-a. In addition, activated T-cells and osteoblasts produce an array of molecules including RANKL, IL-6, IFN-γ and colony stimulating factors (M-CSF, G-CSF, GM-CSF) that can promote osteoclastogenesis and bone resorption, and activation of osteoblasts decreases the production of the RANKL decoy receptor OPG. Finally, bacteria can induce the apoptotic death of osteoblasts either directly via the NLRP3 inflammasome, or indirectly via the autocrine/paracrine actions of released TRAIL interacting with death receptors (DR) expressed on the surface of challenged cells. Since OPG also functions as a decoy receptor for TRAIL, the decreased production of this molecule by infected osteoblasts could exacerbate TRAIL-induced apoptosis leading to decreased numbers of this bone forming population and greater bone loss at sites of infection.