Staphylococcus aureus Protein A Plays a Critical Role in Mediating Bone Destruction and Bone Loss in Osteomyelitis

Abstract

Staphylococcus aureus is the most frequent causative organism of osteomyelitis. It is characterised by widespread bone loss and bone destruction. Previously we demonstrated that S. aureus protein A (SpA) is capable of binding to tumour necrosis factor receptor-1 expressed on pre-osteoblastic cells, which results in signal generation that leads to cell apoptosis resulting in bone loss. In the current report we demonstrate that upon S. aureus binding to osteoblasts it also inhibits de novo bone formation by preventing expression of key markers of osteoblast growth and division such as alkaline phosphatase, collagen type I, osteocalcin, osteopontin and osteocalcin. In addition, S. aureus induces secretion of soluble RANKL from osteoblasts which in turn recruits and activates the bone resorbing cells, osteoclasts. A strain of S. aureus defective in SpA failed to affect osteoblast growth or proliferation and most importantly failed to recruit or activate osteoclasts. These results suggest that S. aureus SpA binding to osteoblasts provides multiple coordinated signals that accounts for bone loss and bone destruction seen in osteomyelitis cases. A better understanding of the mechanisms through which S. aureus leads to bone infection may improve treatment or lead to the development of better therapeutic agents to treat this notoriously difficult disease.

Impact of sarA and Phenol-Soluble Modulins on the Pathogenesis of Osteomyelitis in Diverse Clinical Isolates of Staphylococcus aureus

“…*, statistical significance compared to the results observed with the isogenic parent strain in both cell types. tracellular forms (41,42) and was previously shown to bind to preosteoblastic cells via tumor necrosis factor alpha receptor 1, resulting in apoptosis and, ultimately, bone loss (43). Thus, protein A was present in increased amounts in UAMS-1 relative to the amounts in LAC (Spa in Table 1) and could have contributed to the virulence of UAMS-1, and elimination of PSM production in UAMS-1 had comparatively little impact in this model.…”

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

“…SpA can promote binding to osteoblasts, which results in activation of osteoclasts and inhibition of osteoblast proliferation and mineralization. In addition, SpA binding to osteoblasts induces apoptosis via caspase 6 activation (Claro et al, 2011;Widaa et al, 2012). These effects are believed to contribute to the bone loss observed in osteomyeltitis patients.…”

“…Finally, we demonstrated that SpA binding to osteoblasts generates a signal that induces osteoblast apoptosis. Deletion of SpA from S. aureus prevented these events from occurring, suggesting that the S. aureus SpA-osteoblast interaction is a critical event in upsetting normal bone remodelling (Claro et al, 2011;Widaa et al, 2012).…”

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

“…Bone remodeling is necessary for skeletal growth and the maintenance of bone structure, and it depends on the balance between bone resorption and formation [3]. The resorption of bone by osteoclasts is followed by new bone formation by osteoblasts in a complex cascade of events involving several factors [4]. The maturation of osteoblasts is characterized by the expression of alkaline phosphatase (ALP), which is important for bone matrix deposition and mineralization, whereas differentiated mature osteoblasts produce osteocalcin and osteopontin to regulate matrix mineralization [5,6].…”

“…It is an opportunistic pathogen capable of producing a large number of virulence factors that mediate its attachment to host cells. The infection of bone tissue alters the bone remodeling process regulated by osteoblasts and osteoclasts [4,9]. S. aureus is internalized by phagocytic vesicles in osteoblasts, protecting the bacteria from immune or antibiotic attack and leading to osteoblast apoptosis and the prevention of new bone formation [10,11].…”