Staphylococcus aureus protein A binding to osteoblast tumour necrosis factor receptor 1 results in activation of nuclear factor kappa B and release of interleukin-6 in bone infection

Abstract

Staphylococcus aureus is the major pathogen among the staphylococci and the most common cause of bone infections. These infections are mainly characterized by bone destruction and inflammation, and are often debilitating and very difficult to treat. Previously we demonstrated that S. aureus protein A (SpA) can bind to osteoblasts, which results in inhibition of osteoblast proliferation and mineralization, apoptosis, and activation of osteoclasts. In this study we used small interfering RNA (siRNA) to demonstrate that osteoblast tumour necrosis factor receptor-1 (TNFR-1) is responsible for the recognition of and binding to SpA. TNFR-1 binding to SpA results in the activation of nuclear factor kappa B (NFkB). In turn, NFkB translocates to the nucleus of the osteoblast, which leads to release of interleukin 6 (IL-6). Silencing TNFR-1 in osteoblasts or disruption of the spa gene in S. aureus prevented both NFkB activation and IL-6 release. As well as playing a key role in proinflammatory reactions, IL-6 is also an important osteotropic factor. Release of IL-6 from osteoblasts results in the activation of the bone-resorbing cells, the osteoclasts. Consistent with our results described above, both silencing TNFR-1 in osteoblasts and disruption of spa in S. aureus prevented osteoclast activation. These studies are the first to demonstrate the importance of the TNFR-1-SpA interaction in bone infection, and may help explain the mechanism through which osteoclasts become overactivated, leading to bone destruction. Anti-inflammatory drug therapy could be used either alone or in conjunction with antibiotics to treat osteomyelitis or for prophylaxis in high-risk patients.

Staphylococcus epidermidis serine–aspartate repeat protein G (SdrG) binds to osteoblast integrin alpha V beta 3

“…Both S. aureus and S. epidermidis are also capable of binding directly to osteoblasts in the absence of matrix proteins. S. aureus protein A binds directly to osteoblast Tumour Necrosis Factor Receptor 1 resulting in inhibition of proliferation and induction of apoptosis, contributing to the bone loss seen in osteomyelitis patients [17,19]. S. epidermidis SdrG on the other hand binds directly to osteoblast integrin aVb3.…”

The Macrophage Inflammatory Proteins MIP1α(CCL3) and MIP2α(CXCL2) in Implant-Associated Osteomyelitis: Linking Inflammation to Bone Degradation

“…LTA most likely activates the osteoblasts via toll-like receptor 2, whereas staphylococci express in addition to LTA also other surface molecules which may mediate binding and activation of target cells. Among those is protein A on S. aureus which binds to the tumor necrosis factor α receptor on osteoblasts [46, 47]. Others include fibronectin-binding proteins which are expressed by bacteria and mediate binding to surface-associated fibronectin on osteoblasts [48–50].…”

Apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis

“…Furthermore, biofilm components from a clinical S. aureus strain have recently been demonstrated to induce osteoblast RANKL production and increase the RANKL/OPG ratio in culture media (Sanchez et al, 2013). In particular, staphylococcus protein A (SpA) has been reported to bind to TNF receptor 1 (TNFR1) on osteoblasts (Claro et al, 2013), and S. aureus -induced increases in osteoblast RANKL expression are not seen with SpA mutants (Claro et al, 2011). However, one study suggests that S. aureus surface-associated material can promote osteoclast formation in vitro in a RANKL independent manner (Lau et al, 2006), while another indicates that LPS-induced bone resorption can occur independent of RANKL or the inflammatory mediators IL-1β or TNF-α (Suda et al, 2002).…”