The host response to bacterial bone infection involves a local upregulation of several acute phase proteins.

Bone infections often become chronic and can be difficult to diagnose. In the present study, the osseous gene expression of several acute phase proteins (APPs) during osteomyelitis was investigated in a porcine model of implant associated osteomyelitis (IAO) (sampled 5, 10 and 15 days after infection) and in slaughter pigs with spontaneous hematogenous osteomyelitis, and compared to gene expression in liver tissue. Furthermore, immunohistochemical (IHC) staining of the APP complement component C3 (C3) was performed on the porcine osteomyelitis lesions together with material from human patients with chronic osteomyelitis. In the porcine bone samples a local upregulation of the expression of several APP genes, including serum amyloid A (SAA) and C3, was observed during infection. In the liver, only C-reactive protein (CRP) and Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 were significantly upregulated. Serum concentrations of CRP, SAA and haptoglobin were only upregulated at day 5 in infected animals of the IAO model. This indicates a limited systemic response to osteomyelitis. Similar numbers of positive IHC stained C3 leukocytes were found in human and porcine bone samples with chronic osteomyelitis, indicating a high transcriptional value of porcine models of osteomyelitis. The local upregulation of APPs could potentially be used for diagnosing osteomyelitis.

The inflammatory response to bone infection - a review based on animal models and human patients.

Bone infections are difficult to diagnose and treat, especially when a prosthetic joint replacement or implant is involved. Bone loss is a major complication of osteomyelitis, but the mechanism behind has mainly been investigated in cell cultures and has not been confirmed in human settings. Inflammation is important in initiating an appropriate immune response to invading pathogens. However, many of the signaling molecules used by the immune system can also modulate bone remodeling and contribute to bone resorption during osteomyelitis. Our current knowledge of the inflammatory response relies heavily on animal models as research based on human samples is scarce. Staphylococcus aureus is one of the most common causes of bone infections and is the pathogen of choice in animal models. The regulation of inflammatory genes during prosthetic joint infections and implant-associated osteomyelitis has only been studied in rodent models. It is important to consider the validity of an animal model when results are extrapolated to humans, and both bone composition and the immune system of pigs has been shown to be more similar to humans, than to rodents. Here in vivo studies on the inflammatory response to prosthetic joint infections and implant-associated osteomyelitis are reviewed.

Pigs are useful for the molecular study of bone inflammation and regeneration in humans.

Pigs are used with increased frequency to model different kinds of orthopedic surgical conditions. In order to show the full potential of porcine models in orthopedic research, it is therefore required to examine the expression of bone regulatory genes in pigs affected by orthopedic surgery and compare it to the expression in humans and mice as mice, are one of the most applied animal species in orthopedics today. In the present study, the local molecular response to drilling of a tibial implant cavity, and the subsequent insertion of a steel implant was examined in a porcine model. Pigs were euthanized five days after drilling of the bone. The molecular response of 73 different genes was analyzed using a high-throughput quantitative polymerase chain reaction platform and compared to histopathology. Histologically, it was found that bone remodeling was initiated on day 5 after surgery and was associated with upregulation of several genes involved in bone degradation and formation ( CTSK, ACP5, IBSP, RANK, RANKL and COL1A1). Interleukin-6 and several acute-phase proteins (C3, SAA and ITIH4) were significantly upregulated, indicating their importance in the initial process of healing and osseointegration. All tested bone morphogenic proteins (BMP2, -4 and -7) including their inhibitor noggin were also significantly upregulated. Surprisingly, vascular endothelial growth factor A was not found to be regulated five days after surgery while several other vascular growth factors (ANGPT1, ANGPT2 and PTN) were upregulated. The pig was found to be a useful model for elucidation of bone regulatory genes in humans.