The osteoblast secretome in Staphylococcus aureus osteomyelitis

Abstract

Osteomyelitis (OM) is an infectious disease of the bone predominantly caused by the opportunistic bacterium Staphylococcus aureus (S. aureus). Typically established upon hematogenous spread of the pathogen to the musculoskeletal system or contamination of the bone after fracture or surgery, osteomyelitis has a complex pathogenesis with a critical involvement of both osteal and immune components. Colonization of the bone by S. aureus is traditionally proposed to induce functional inhibition and/or apoptosis of osteoblasts, alteration of the RANKL/OPG ratio in the bone microenvironment and activation of osteoclasts; all together, these events locally subvert tissue homeostasis causing pathological bone loss. However, this paradigm has been challenged in recent years, in fact osteoblasts are emerging as active players in the induction and orientation of the immune reaction that mounts in the bone during an infection. The interaction with immune cells has been mostly ascribed to osteoblast-derived soluble mediators that add on and synergize with those contributed by professional immune cells. In this respect, several preclinical and clinical observations indicate that osteomyelitis is accompanied by alterations in the local and (sometimes) systemic levels of both pro-inflammatory (e.g., IL-6, IL-1α, TNF-α, IL-1β) and anti-inflammatory (e.g., TGF-β1) cytokines. Here we revisit the role of osteoblasts in bacterial OM, with a focus on their secretome and its crosstalk with cellular and molecular components of the bone microenvironment and immune system.

B. abortus Infection Promotes an Imbalance in the Adipocyte–Osteoblast Crosstalk Favoring Bone Resorption

“…This process involves RANKL, a molecule displayed on the membrane of osteoblasts that stimulates differentiation and resorptive activity of osteoclasts, leading to bone resorption. Previous studies on the interaction between bacteria and osteoblasts also found an increase in RANKL [ 36 , 54 , 55 ]. Culture supernatants from B. abortus -infected adipocytes induce RANKL expression in osteoblasts.…”

Ultrastructural Evidence of Mitochondrial Dysfunction in Osteomyelitis Patients

“…Interestingly, an increase in mitochondrial fission in osteoblasts is also linked to an increase in the ratio of receptor activator of nuclear factor-kappaB ligand (RANKL) to osteoprotegerin (OPG) [ 54 ]. The RANKL/OPG ratio is a determinant of bone mass and skeletal integrity [ 55 ]. Thus, increased fission is connected to additional bone destruction, which furthermore suggests that the inhibition of fission might offer promising results in the treatment of osteomyelitis.…”

Periprosthetic joint infection and immunity: Current understanding of host–microbe interplay

“…169 SCVs have also been detected in fibroblasts isolated from hip implant infections with prior treatment failures. 170 In response to S. aureus infections, osteoblasts produce host defense molecules including AMPs (LL-37 and β-defensins), upregulates TLR2 expression and a multitude of cytokines and chemokines important in immune recruitment (IL-6, IL-1β, TNF-α, CXCL10, CXCL9, CCL5) 162,171,172 (extensively reviewed in Granata et al 173 ).…”

“…In response to S. aureus infections, osteoblasts produce host defense molecules including AMPs (LL‐37 and β‐defensins), upregulates TLR2 expression and a multitude of cytokines and chemokines important in immune recruitment (IL‐6, IL‐1β, TNF‐α, CXCL10, CXCL9, CCL5) 162,171,172 (extensively reviewed in Granata et al 173 ). Osteocytes also produce lipid mediators (prostaglandins) and cytokines (IL‐6) increase osteoblast antimicrobial efficiency 162 .…”