Staphylococcus aureus vs. Osteoblast: Relationship and Consequences in Osteomyelitis

Abstract

Bone cells, namely osteoblasts and osteoclasts work in concert and are responsible for bone extracellular matrix formation and resorption. This homeostasis is, in part, altered during infections by Staphylococcus aureus through the induction of various responses from the osteoblasts. This includes the over-production of chemokines, cytokines and growth factors, thus suggesting a role for these cells in both innate and adaptive immunity. S. aureus decreases the activity and viability of osteoblasts, by induction of apoptosis-dependent and independent mechanisms. The tight relationship between osteoclasts and osteoblasts is also modulated by S. aureus infection. The present review provides a survey of the relevant literature discussing the important aspects of S. aureus and osteoblast interaction as well as the ability for antimicrobial peptides to kill intra-osteoblastic S. aureus, hence emphasizing the necessity for new anti-infectious therapeutics.

Keywords: Staphylococcus aureus; antibiotics; antimicrobial peptide; inflammation; internalization; osteoblast; phenol soluble modulin; small colony variants.

Figure 1

Staphylococcus aureus interaction with BEM. Staphylococcus aureus can interact with the BEM to concentrate around osteoblasts. Collagen adhesin (Cna) links with type I collagen, bone sialoprotein binding protein (Bbp) links with bone sialoprotein, MHC II analog protein (Map) can potentially link osteopontin. Fibronectin binding proteins A and B (FnBP A/B) link with fibronectin and act as bridges between Staphylococcus aureus and osteoblasts through α5β1 integrin.

Figure 2

Staphylococcus aureus signaling mechanism after contact and internalization by osteoblasts. After internalization, Staphylococcus aureus can escape from vesicle, be disrupted from inside the vesicle or persist inside osteoblasts through a SCV phenotype. Staphylococcus aureus can also interact with extracellular receptors TLR2 and TNFR-1 and with intracellular receptors TLR9 and NODs after its internalization into osteoblasts thanks to α5β1 integrin and actin filaments.

Figure 3

Staphylococcus aureus induction of inflammatory mediator production by osteoblasts and participation in the recruitment/activation of innate and adaptive immune cells. Staphylococcus aureus interaction with osteoblasts increases the expression of cytokines IL-1β, IL-18, TNF-α, the production and release of IL-6, IL-12 and the expression and release of chemokines CXCL2, CXCL8, CXCL10, CCL2, CCL3, CCL5 and growth factors G-CSF and GM-CSF. It also increases the expression and production of CD40 and MHC II. All of this participates to the recruitment and activation of innate (neutrophils, monocytes/macrophages) and adaptive (lymphocytes) immune cells.

Figure 4

Staphylococcus aureus induction of osteoblast death. Staphylococcus aureus can cause the necrosis of osteoblasts through the release of membrane-damaging virulence factors such as PSMs. It can also induce the apoptosis of osteoblasts through intrinsic and extrinsic caspase pathways. Both can lead to the release of intracellular Staphylococcus aureus, which can re-infect other osteoblasts.

Figure 5

Induction of osteoclastogenesis by Staphylococcus aureus-challenged osteoblasts. S. aureus-challenged osteoblasts increase their expression and production of RANK-L, directly or through the COX-2/PGE2 pathway. It leads to an excessive formation and activation of osteoclasts and to a severe bone resorption in addition to a decreased production of OPG.

Figure 6

Summary diagram of the osteoblasts responses in presence of Staphylococcus aureus. S. aureus can interact with osteoblasts and provoke: inflammation by increased release of mediators such as cytokines (CTKs), chemokines (CMKs), or growth factors (GFs); osteoblast self-defense by the production of AMPs (HBD-2/3, LL-37); osteoblasts death through apoptosis or necrosis; bone resorption by activation of the RANK/RANK-L complex.