The effect of TNF-α on osteoblasts in metal wear-induced periprosthetic bone loss.

AIMS: This study aimed to examine the effects of tumour necrosis factor-alpha (TNF-α) on osteoblasts in metal wear-induced bone loss. METHODS: TNF-α immunoexpression was examined in periprosthetic tissues of patients with failed metal-on-metal hip arthroplasties and also in myeloid MM6 cells after treatment with cobalt ions. Viability and function of human osteoblast-like SaOs-2 cells treated with recombinant TNF-α were studied by immunofluorescence, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay, western blotting, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Macrophages, lymphocytes, and endothelial cells displayed strong TNF-α immunoexpression in periprosthetic tissues containing metal wear debris. Colocalization of TNF-α with the macrophage marker CD68 and the pan-T cell marker CD3 confirmed TNF-α expression in these cells. Cobalt-treated MM6 cells secreted more TNF-α than control cells, reflecting the role of metal wear products in activating the TNF-α pathway in the myeloid cells. While TNF-α did not alter the immunoexpression of the TNF-receptor 1 (TNF-R1) in SaOs-2 cells, it increased the release of the soluble TNF-receptor 1 (sTNF-R1). There was also evidence for TNF-α-induced apoptosis. TNF-α further elicited the expression of the endoplasmic reticulum stress markers inositol-requiring enzyme (IRE)-1α, binding-immunoglobulin protein (BiP), and endoplasmic oxidoreductin1 (Ero1)-Lα. In addition, TNF-α decreased pro-collagen I α 1 secretion without diminishing its synthesis. TNF-α also induced an inflammatory response in SaOs-2 cells, as evidenced by the release of reactive oxygen and nitrogen species and the proinflammatory cytokine vascular endothelial growth factor. CONCLUSION: The results suggest a novel osteoblastic mechanism, which could be mediated by TNF-α and may be involved in metal wear debris-induced periprosthetic bone loss. Cite this article: Bone Joint Res 2020;9(11):827-839.

Reactive oxygen/nitrogen species (ROS/RNS) and oxidative stress in arthroplasty.

The interplay between implant design, biomaterial characteristics, and the local microenvironment adjacent to the implant is of utmost importance for implant performance and success of the joint replacement surgery. Reactive oxygen and nitrogen species (ROS/RNS) are among the various factors affecting the host as well as the implant components. Excessive formation of ROS and RNS can lead to oxidative stress, a condition that is known to damage cells and tissues and also to affect signaling pathways. It may further compromise implant longevity by accelerating implant degradation, primarily through activation of inflammatory cells. In addition, wear products of metallic, ceramic, polyethylene, or bone cement origin may also generate oxidative stress themselves. This review outlines the generation of free radicals and oxidative stress in arthroplasty and provides a conceptual framework on its implications for soft tissue remodeling and bone resorption (osteolysis) as well as implant longevity. Key findings derived from cell culture studies, animal models, and patients' samples are presented. Strategies to control oxidative stress by implant design and antioxidants are explored and areas of controversy and challenges are highlighted. Finally, directions for future research are identified. A better understanding of the host-implant interplay and the role of free radicals and oxidative stress will help to evaluate therapeutic approaches and will ultimately improve implant performance in arthroplasty.

Bone biology in postnatal Wistar rats following hypoxia-reoxygenation.

Hypoxia response pathways have a central role in normal and abnormal bone biology but the effect of systemic hypoxia-reoxygenation on bone is not clear. Following hypoxic exposure, aberrant synthesis, folding and trafficking of proteins has been reported to occur, which can result in endoplasmic reticulum (ER) stress and may finally cause cell death. This study aimed to examine the effect of systemic hypoxia-reoxygenation injury on bone biology in postnatal rats. Immunoexpression of HIF-1α and VEGF was upregulated in femurs of newborn Wistar rats in response to systemic hypoxia-reoxygenation. Along with that, increased apoptosis of osteoblast precursors, osteoblasts, osteocytes and endothelial cells was observed in comparison to femurs of control animals by transmission electron microscopy, TUNEL staining and immunoexpression of cleaved caspase-3. The viability of osteoclasts was not affected. After hypoxia-reoxygenation, ER stress was observed in the osteoblasts and osteocytes as indicated by dilatation of the ER and enhanced immunoexpression of the ER stress marker GRP78. Localisation of collagen α1 immunoreaction was widespread in the bone matrix of control femurs but was confined to the osteoblasts and osteocytes in response to hypoxia-reoxygenation. In support of these findings, in vitro work showed reduced viability of osteoblast-like SaOs-2 cells and upregulation of GRP78 protein expression in them by western blotting following exposure to hypoxia. This suggests that systemic hypoxia-reoxygenation may disturb bone biology in postnatal Wistar rats by inducing ER stress and apoptosis in osteoblasts and osteocytes, without affecting the viability of osteoclasts. More in-depth research is needed to confirm causality between ER stress and apoptosis of osteoblasts and osteocytes.

Screw Track Osteolysis in the Cementless Total Knee Replacement Design.

BACKGROUND: There is a paucity of reports on osteolysis associated with tibial screw fixation in cementless total knee arthroplasty (TKA), and the pathophysiology is not clear. This study aimed to describe the pathology related to screw track osteolysis around the tibia in cementless TKA. METHODS: The study cohort comprised 100 revised cementless TKAs with tibial screw fixation. Screw track osteolysis and various screw angles were analyzed radiologically. Tissue samples from the joint capsule and the osteolytic cavity were investigated for metal/polyethylene wear. The type of tissue response was determined using immunohistochemistry. Retrieved tibial polyethylene inserts were analyzed for screw hole impression and mode of wear. Tissue metal content was measured by inductively coupled plasma optical emission spectrometry. Electrochemical reactions between the tibial tray and the cancellous screws were investigated. RESULTS: Radiological analysis showed screw track osteolysis predominantly at the medial aspect of the tibial component, and the severity of osteolysis positively correlated with smaller medial proximal tibial screw angles. Osteolysis was associated with high titanium concentrations but not with polyethylene particles. An open circuit potential between the screw and the tibial base plate was measured. Necrosis, osteolytic cyst formation and macrophages, T and B cells, and dendritic cells were present. CONCLUSION: The present study highlights the risk for screw track osteolysis in cementless TKA with screw fixation. Our data collectively suggest that titanium wear may contribute to screw track osteolysis in the cementless TKA design. The contribution of screw angles is difficult to prove.

What Is the Role of Diagnostic and Therapeutic Sonication in Periprosthetic Joint Infections?

BACKGROUND: Periprosthetic joint infection (PJI) is one of the most dreaded complications in joint replacement surgery. Diagnosis and treatment can be difficult and biofilms are of major concern due to their low susceptibility toward antibiotics. METHODS: This review focuses on the use of sonication as an evolving diagnostic and adjunct treatment modality in the context of PJI. Therapeutic application of sonication is discussed separately for its (i) direct action on bacteria, (ii) synergistic effects with antibiotics, and (iii) effects on release of antibiotics from bone cement. RESULTS: Used as a diagnostic tool, sonication shows promising results with respect to sensitivity and specificity when compared to conventional methods, notably after previous administration of antibiotics. As an adjunct treatment modality, the chemical, physical, and mechanical effects of sonication are primarily driven by cavitation and recognized as the main cause for bactericidal effects but the exact underlying mechanisms have not been identified yet. Sonication alone does not have the ability to completely eradicate biofilms but synergistic effects when used in conjunction with antibiotics have been reported. There is also evidence for enhanced antibiotic release from bone cement. CONCLUSION: Sonication is as an evolving modality in the context of PJIs. As a diagnostic tool, it has not been introduced in routine clinical practice and sonication as a treatment modality in PJIs is still in an experimental stage. Factors such as frequency, pressure, chemical activity, intensity, and exposure time need to be evaluated for optimal application of sonication and may also improve study comparison.

Ballooning osteolysis in 71 failed total ankle arthroplasties.

Background and purpose - Aseptic loosening is a major cause of failure in total ankle arthroplasty (TAA). In contrast to other total joint replacements, large periarticular cysts (ballooning osteolysis) have frequently been observed in this context. We investigated periprosthetic tissue responses in failed TAA, and performed an element analysis of retrieved tissues in failed TAA. Patients and methods - The study cohort consisted of 71 patients undergoing revision surgery for failed TAA, all with hydroxyapatite-coated implants. In addition, 5 patients undergoing primary TAA served as a control group. Radiologically, patients were classified into those with ballooning osteolysis and those without, according to defined criteria. Histomorphometric, immunohistochemical, and elemental analysis of tissues was performed. Von Kossa staining and digital microscopy was performed on all tissue samples. Results - Patients without ballooning osteolysis showed a generally higher expression of lymphocytes, and CD3+, CD11c+, CD20+, and CD68+ cells in a perivascular distribution, compared to diffuse expression. The odds of having ballooning osteolysis was 300 times higher in patients with calcium content >0.5 mg/g in periprosthetic tissue than in patients with calcium content ≤0.5 mg/g (p < 0.001). Interpretation - There have been very few studies investigating the pathomechanisms of failed TAA and the cause-effect nature of ballooning osteolysis in this context. Our data suggest that the hydroxyapatite coating of the implant may be a contributory factor.

Low-frequency sonication may alter surface topography of endoprosthetic components and damage articular cartilage without eradicating biofilms completely.

Two-stage exchange arthroplasty is the current standard of care for arthroplasty-related infections. Reinfection rates up to 30% are reported, and there is significant morbidity for the patient. In cases of failure, arthrodesis or amputation may result. Ultrasonic treatment has the potential to eradicate biofilms and avoid two-stage exchange arthroplasty. Data in the specific context of arthroplasty infections is scant, and there is debate regarding optimal frequency and intensity of treatment. Surface topography alterations of the endoprosthetic components and damage to adjacent bone and cartilage have not been investigated. We found incomplete biofilm eradication and significant increase in surface roughness (maximum peak-to-valley height) of cobalt-chrome unicondylar knee components as well as reduction in articular cartilage thickness area from 10 retrieved femoral heads after low-frequency sonication treatment according to manufacturer-specified recommendations. Our data collectively suggest that sonication treatment for biofilm eradication in arthroplasty infections may not be effective and surface topography alterations may potentially reduce implant longevity.