With the aging of population, the number of indications for total joint replacement is continuously increasing. However, prosthesis loosening can happen and is related to two major mechanisms: (1) aseptic loosening due to prosthesis micromotion and/or corrosion and release of wear particles from the different components of the implanted material and (2) septic loosening due to chronic prosthetic joint infection (PJI). The "aseptic" character of prosthesis loosening has been challenged over the years, especially considering that bacteria can persist in biofilms and be overlooked during diagnosis. Histological studies on periprosthetic tissue samples reported that macrophages are the principle cells associated with aseptic loosening due to wear debris. They produce cytokines and favor an inflammatory environment that induces formation and activation of osteoclasts, leading to bone resorption and periprosthetic osteolysis. In PJIs, the presence of infiltrates of polymorphonuclear neutrophils is a major criterion for histological diagnosis. Neutrophils are colocalized with osteoclasts and zones of osteolysis. A similar inflammatory environment also develops, leading to bone resorption through osteoclasts. Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis are the main staphylococci observed in PJIs. They share the common feature to form biofilm. For S. aureus and S. epidermidis, the interaction between biofilm and immunes cells (macrophages and polymorphonuclear neutrophils) differs regarding the species. Indeed, the composition of extracellular matrix of biofilm seems to impact the interaction with immune cells. Recent papers also reported the major role of myeloid-derived suppressor cells in biofilm-associated PJIs with S. aureus. These cells prevent lymphocyte infiltration and facilitate biofilm persistence. Moreover, the role of T lymphocytes is still unclear and potentially underestimates. In this review, after introducing the cellular mechanism of aseptic and septic loosening, we will focus on the interrelationships between staphylococcal biofilm, immune cells, and bone cells.

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Interaction Between Staphylococcal Biofilm and Bone: How Does the Presence of Biofilm Promote Prosthesis Loosening?

The osteoclast, a target cell for microorganisms.

We used a murine model of postsurgical osteomyelitis (OM) to evaluate the relative virulence of the Staphylococcus aureus strain LAC and five isogenic variants that differ in the functional status ...

https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.9b00291

Exploiting Correlations between Protein Abundance and the Functional Status of saeRS and sarA To Identify Virulence Factors of Potential Importance in the Pathogenesis of Staphylococcus aureus Osteomyelitis

Biomimetic 3D in vitro model of biofilm triggered osteomyelitis for investigating hematopoiesis during bone marrow infections.

The treatment of infected bone defects is an intractable problem in orthopedics. It comprises two critical parts, namely that of infection control and bone defect repair. According to these two core tasks during treatment, the ideal approach of simultaneously controlling infection and repairing bone defects is promising treatment strategy. Several engineered biomaterials and drug delivery systems with dual functions of anti-bacterial action and ostogenesis-promotion have been developed and demonstrated excellent therapeutic effects. Compared with the conventional treatment method, the dual-functional composite scaffold can provide one-stage treatment avoiding multiple surgeries, thereby remarkably simplifying the treatment process and reducing the treatment time, overcoming the disadvantages of conventional bone transplantation. In this review, the impaired bone repair ability and its specific mechanisms in the microenvironment of pathogen infection and excessive inflammation were analyzed, providing a theoretical basis for the treatment of infectious bone defects. Furthermore, we discussed the composite dual-functional scaffold composed of a combination of antibacterial and osteogenic material. Finally, a series of advanced drug delivery systems with antibacterial and bone-promoting capabilities were summarized and discussed. This review provides a comprehensive understanding for the microenvironment of infectious bone defects and leading-edge design strategies for the antibacterial and bone-promoting dual-function scaffold, thus providing clinically significant treatment methods for infectious bone defects. 

https://doi.org/10.1016/j.mtbio.2022.100409

Dual-functional composite scaffolds for inhibiting infection and promoting bone regeneration

Staphylococcus aureus (S. aureus) is the most common organism causing osteomyelitis, and Staphylococcus aureus protein A (SpA) is an important virulence factor anchored in its cell wall. However, the precise mechanisms underlying the bone loss caused by SpA have not been well understood. The present study aimed to investigate the effect of SpA on osteoclast differentiation, and the probable mechanism was investigated. Raw264.7 cells were treated with SpA in the absence or presence of receptor‑activated (NF)‑κB ligand for 5 days, and morphological and biochemical assays were used to assess osteoclastogenesis and explore the underlying mechanisms. Data demonstrated that SpA induced osteoclast differentiation and promoted bone resorption in a dose‑dependent manner in the absence or presence of RANKL. In addition, the expression of osteoclast‑specific genes, such as the tartrate resistant acid phosphatase, matrix metalloproteinase‑9, cathepsin K, calcitonin receptors and d2 isoform of the vacuolar ATPase Vo domain, were enhanced by SpA. Furthermore, the SpA‑induced osteoclast differentiation was associated with the degradation of inhibitor of κB‑α, phosphorylation of NF‑κB p65 and increased expression of nuclear factor of activated T‑cells. However, by treatment with JSH‑23, an NF‑κB inhibitor, the formation of osteoclast‑like cells and resorption pits was significantly reduced, and the expression of osteoclast‑specific genes was also inhibited. Collectively, in the present study SpA induced osteoclast differentiation, promoted bone resorption, and the NF‑κB signaling pathway was involved in this process.

https://www.spandidos-publications.com/10.3892/mmr.2017.7316/download

Li‑Rong Ren

Papers

Staphylococcus aureus Protein A induces osteoclastogenesis via the NF‑κB signaling pathway