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.

Involvement of Toll-Like Receptor 2 and Pro-Apoptotic Signaling Pathways in Bone Remodeling in Osteomyelitis

“…Osteoblasts express members of the TLR family of PAMPs, which recognize microbial pathogens leading to the release of inflammatory cytokines [33,34]. However, intracellular sensors such as NOD1 and NOD2 also play a role in the recognition of intracellular pathogens [35,36], and the induction of osteoblast apoptosis requires the cooperative action of cell surface and intracellular molecules [35]. The signaling pathways triggered by TLR2 involve the activation of the transcription factor NF-κB and JNK, which initiates the transcription of proinflammatory cytokine genes [37,38,39].…”

Conservative treatment in a patient with diabetic osteomyelitis: antibiotic treatment is sufficient for complete bone regeneration in selected cases

“…Infiltrating inflammatory leucocytes release a large number of proteolytic enzymes dissolving bone mineral. S. aureus infection leads to increased production of inflammatory cytokines, altering the balance between osteoblastic and osteoclastic cell functions, thus inhibiting bone formation and enhancing bone resorption 7. Subsequent to antibiotic treatment, our patient regenerated the distal phalanx with regular shape and full mineralisation.…”

“…Several mechanisms of staphylococcal osteomyelitis explain the loss of mineralisation 7. Infiltrating inflammatory leucocytes release a large number of proteolytic enzymes dissolving bone mineral.…”

Microbial Modulation of Host Apoptosis and Pyroptosis

“…While (Cunha and Zamboni, 2013) summarizes the subversion of inflammasome activation and pyroptosis by eight pathogenic bacteria, (Malireddi and Kanneganti, 2013) introduces the role of type I interferons in inflammasome activation and cell death induced by microbial infections. The apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis is reviewed in Marriott (2013). The intestinal epithelial cell apoptosis in the setting of altered microbiota with enteral nutrient deprivation is reviewed in Demehri et al (2013).…”

“…How cell death can lead to human disease conditions is well described by the review paper (Marriott, 2013) that focuses on osteomyelitis, a severe infection of bone caused by S. aureus and Salmonella spp. Osteomyelitis is often associated with bone resorption and progressive inflammatory destruction.…”