Failure Of Total Joint Arthroplasty Research Articles

Melittin Treats Periprosthetic Osteolysis in a Rat Model by Inhibiting the NF-kB Pathway and Regulating the Ratio of Receptor Activator of Nuclear Factor Kappa B Ligand/Osteoprotegerin

BackgroundAseptic loosening around the prosthesis is a common cause of failure in total joint arthroplasty. Polyethylene wear particles trigger the release of inflammatory factors by macrophages. Key mediators involved in osteoclastogenesis include interleukin-6, tumor necrosis factor-α, receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL), and bone protection hormone (Osteoprotegerin [OPG]). The purpose of our experiment was to see whether melittin can slow down the release of inflammatory mediators through the NF-kB pathway, regulate the RANKL/OPG ratio, reduce osteoclast formation, and delay the onset of arthritis in rats. MethodsA total of 20 male Sprague-Dawley rats (10 months, Specific Pathogen Free, 350 g ± 20 g) were randomly divided into 5 groups: sham group, model group, melittin concentration 1 group (0.2 mg/kg), concentration 2 group (0.4 mg/kg), and concentration 3 group (0.6 mg/kg). All rats were implanted with TA2 high-purity titanium rods. A drill was used to create a bone canal along the long axis of the femur in the intercondylar notch. The model group and experimental groups were exposed to polyethylene particles, while the sham group did not receive any particles. ResultsThe melittin group exhibited significantly increased serum levels of serum P, calcium-phosphorus product, OPG, PINP, PINP/CTX-I, and OPG/RANKKL (P < .05). In the experimental group, micro computed tomography scanning results revealed a decrease in the amount of bone defect around the prosthesis. Immunofluorescence analysis demonstrated a decrease in the expression of IKKα and P65, while the expression of OPG showed an upward trend. Both Hematoxylin-Eosin and Tartrate-Resistant Acid Phosphatase staining revealed less osteoclast and inflammatory cell infiltration in bone resorption pits. ConclusionsOur study demonstrates that melittin has the ability to inhibit the NF-kB pathway in a rat model, and reduce the impact of RANKL/OPG, thereby delaying osteoclast activity and alleviating periprosthetic osteolysis.

CD73 inhibits titanium particle-associated aseptic loosening by alternating activation of macrophages.

Aseptic inflammation is a major cause of late failure in total joint arthroplasty, and the primary factor contributing to the development and perpetuation of aseptic inflammation is classical macrophage activation (M1 phenotype polarization) induced by wear particles. CD73 (ecto-5'-nucleotidase) is an immunosuppressive factor that establishes an adenosine-induced anti-inflammatory environment. Although CD73 has been shown to suppress inflammation by promoting alternate macrophage activation (M2 phenotype polarization), its role in wear particle-induced aseptic inflammation is currently unknown. Our experiments were based on metabolomic assay results in a mouse model of aseptic loosening, and studied the function of CD73 in vivo and in vitro using a mouse aseptic loosening model and a mouse bone marrow derived macrophage (BMDM) inflammation model. Results show that aseptic loosening (AL) reduces the purine metabolic pathway and decreases the native expression of the metabolite adenosine. In vivo, CD73 expression was low in the bone tissue surrounding the titanium nail and synovial-like interface tissue, while in vitro experiments demonstrated that CD73 knockdown promoted titanium particles-induced aseptic inflammation. CD73 overexpression mitigated the titanium particle-mediated enhancement of LPS-induced M1 polarization while promoting the titanium particle-mediated attenuation of IL-4-induced M2 polarization. In BMDM exposed to titanium particles, CD73 promotes M2 polarization via the p38 pathway. Meanwhile, local injection of recombinant mouse CD73 protein slightly alleviated the progression of AL. Collectively, our data suggest that CD73 alleviates the process of AL, and this function is achieved by promoting alternate activation of macrophages.

Global Cluster Analysis and Network Visualization in Prosthetic Joint Infection: A Scientometric Mapping.

Prosthetic joint infection (PJI) is the main reason of failure of total joint arthroplasty (TJA). This study aimed to investigate the global trends and network visualization in research of PJI. Publications in PJI search during 1980-2022 were extracted from the Science Citation Index-Expanded of Web of Science Core Collection database (WoSCC). The source data was investigated and analyzed by bibliometric methodology. For network visualization, VOS viewer and R software was used to perform bibliographic coupling, co-citation, co-authorship and co-occurrence analysis and to predict the publication trends in PJI research. There were 7288 articles included. The number of publications and relative research interests increased gradually per year globally. The USA made the highest contributions in the world and with the highest H-index and the most citations. Journal of Arthroplasty published the highest number of articles in this area. The Mayo Clinic, Thomas Jefferson University (Rothman Institute), Hospital Special Surgery and the Rush University were the most contributive institutions by network visualization. Included studies were divided into four clusters: bacterial pathogenic mechanism and antibacterial drugs study, TJA complications, risk factors and epidemiology of PJI, diagnosis of PJI, and revision surgical management. More articles in PJI could be published over the next few years. The number of publications about PJI will be increasing dramatically based on the global trends and network visualization. The USA made the highest contributions in PJI. Diagnosis and revision management may be the next hot spots in this field.

Povidone-iodine irrigation reduces infection after total hip and knee arthroplasty.

One of the most important challenges faced by orthopedic surgeons is periprosthetic joint infection (PJI). PJI is a common cause for total joint arthroplasty failure with an incidence of 0.3-1.9%. PJI can be devastating for the patient and extremely costly for the healthcare system. There is concern that a major cause of PJI is intra-operative colonization and recent studies have shown a decrease in PJI with the use of dilute povidone-iodine (Betadine®, Avrio Health L.P, Stamford, CT) irrigation prior to wound closure. This study presents our experience with the use of dilute Betadine® irrigation prior to wound closure and its effect on our post-operative hip and knee arthroplasty acute infection rate. Retrospective chart review performed at our hospital looking at PJI amongst patients who underwent primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) between 2013 and 2017 comparing different irrigation methods (n = 3232). The study group (n = 1207) underwent irrigation prior to wound closure with dilute Betadine for 3min and the control group (n = 1511) underwent irrigation using normal saline (NS). Using a logistic regression model where the following variables were adjusted for; ASA, age, sex, foley insertion, surgical duration and diabetes mellitus status a statistical significant reduction was seen in any infection (OR 0.45 [0.22; 0.89], p value < 0.05) and SSI (OR 0.30 [0.13; 0.70], p value 0.01) with the Betadine group. No significant reduction was seen with deep infections with the Betadine group compared to the NS group. PJI is a devastating complication following total joint arthroplasty and we found Betadine compared to NS irrigation provides an inexpensive and simple method to lower any PJI and more specifically SSI in THA and TKA. III.

Effects of the Local Bone Renin-Angiotensin System on Titanium-Particle-Induced Periprosthetic Osteolysis.

Wear particles may induce osteoclast formation and osteoblast inhibition that lead to periprosthetic osteolysis (PPOL) and subsequent aseptic loosening, which is the primary reason for total joint arthroplasty failure. Local bone renin-angiotensin system (RAS) has been found to participate in the pathogenic process of various bone-related diseases via promoting bone resorption and inhibiting bone formation. However, it remains unclear whether and how local bone RAS participates in wear-particle-induced PPOL. In this study, we investigated the potential role of RAS in titanium (Ti) particle-induced osteolysis in vivo and osteoclast and osteoblast differentiation in vitro. We found that the expressions of AT1R, AT2R and ACE in the interface membrane from patients with PPOL and in calvarial tissues from a murine model of Ti-particle-induced osteolysis were up-regulated, but the increase of ACE in the calvarial tissues was abrogated by perindopril. Moreover, perindopril mitigated the Ti-particle-induced osteolysis in the murine model by suppressing bone resorption and increasing bone formation. We also observed in RAW264.7 macrophages that Ang II promoted but perindopril suppressed Ti-particle-induced osteoclastogenesis, osteoclast-mediated bone resorption and expression of osteoclast-related genes. Meanwhile, Ang II enhanced but perindopril repressed Ti-particle-induced suppression of osteogenic differentiation and expression of osteoblast-specific genes in mouse bone marrow mesenchymal stem cells (BMSCs). In addition, local bone RAS promoted Ti-particle-induced osteolysis by increasing bone resorption and decreasing bone formation through modulating the RANKL/RANK and Wnt/β-catenin pathways. Taken together, we suggest that inhibition of RAS may be a potential approach to the treatment of wear-particle-induced PPOL.

Does Symptomatic Benign Prostatic Hyperplasia Increase the Risk of Periprosthetic Joint Infection After Primary Total Joint Arthroplasty?

BackgroundPeriprosthetic joint infection (PJI) is among the leading causes of failure in total joint arthroplasty. A recently proposed risk factor for PJI is symptomatic benign prostatic hyperplasia (sBPH). This study aims to determine if sBPH is associated with PJI following primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). MethodsUsing the Mariner all-payer claims database, 1745 patients with sBPH undergoing primary THA were propensity-matched with 3490 controls, and 3053 patients with sBPH undergoing primary TKA were propensity-matched with 6106 controls. Additionally, the same 1745 patients with sBPH undergoing THA were compared to 317,360 prematched controls, and the same 3053 patients with sBPH undergoing TKA were compared to 557,730 prematched controls. Univariate analysis was conducted using chi-squared or ANOVA where appropriate. ResultsAt two years postoperatively, patients with sBPH were not at significantly increased risk for PJI following primary THA (1.54% vs 1.43%; P = .745) and TKA (1.99% vs 2.14%; P = .642) relative to postmatch controls. Compared to matched controls, THA patients with sBPH had an increased 90-day incidence of anemia (P < .001), blood transfusion (P < .001), and urinary tract infection (UTI; P < .001). Total knee arthroplasty patients with sBPH had an increased 90-day incidence of anemia (P < .001), blood transfusion (P < .001), cellulitis (P = .023), renal failure (P = .030), heart failure (P = .029), and UTI (P < .001) relative to matched controls. ConclusionIn primary THA and TKA, sBPH does not appear to be an independent risk factor for PJI within two years postoperatively. However, clinicians should be cognizant of the significantly increased risk for postoperative UTI in this patient population.

Stevioside Prevents Wear Particle-Induced Osteolysis by Inhibiting Osteoclastogenesis and Inflammatory Response via the Suppression of TAK1 Activation.

Aseptic loosening and periprosthetic osteolysis are the leading causes of total joint arthroplasty failure, which occurs as a result of chronic inflammatory response and enhanced osteoclast activity. Here we showed that stevioside, a natural compound isolated from Stevia rebaudiana, exhibited preventative effects on titanium particle-induced osteolysis in a mouse calvarial model. Further histological assessment and real-time PCR analysis indicated that stevioside prevented titanium particle-induced osteolysis by inhibiting osteoclast formation and inflammatory cytokine expression in vivo. In vitro, we found that stevioside could suppress RANKL-induced osteoclastogenesis and titanium particle-induced inflammatory response in a dose-dependent manner. Mechanistically, stevioside achieved these effects by disrupting the phosphorylation of TAK1 and subsequent activation of NF-κB/MAPKs signaling pathways. Collectively, our data suggest that stevioside effectively suppresses osteoclastogenesis and inflammatory response both in vitro and in vivo, and it might be a potential therapy for particle-induced osteolysis and other osteolytic diseases.

Vitamin-D Supplementation: A Low-Risk, High-Gain Therapy to Prevent PJI?: Commentary on an article by Vishal Hegde, MD, et al.: "Single-Dose, Preoperative Vitamin-D Supplementation Decreases Infection in a Mouse Model of Periprosthetic Joint Infection".

Commentary Total joint arthroplasties are common and can be compromised by periprosthetic joint infections (PJIs) that are primarily bacterial in nature. Could the solution to this problem be as simple as taking a vitamin D pill? The study by Hegde and colleagues suggests that it just might help. Vitamin D comes in many forms. The U.S. Food and Drug Administration (FDA) has approved oral 25-hydroxyvitamin D3 (25D3), which is converted inside cells to the active metabolite 1,25-dihydroxyvitamin D3 (1,25D3). In this basic science study, Hegde and colleagues investigated 25D3 supplementation in a mouse model of PJI. Their data reveal that intraperitoneal supplementation with 25D3 may have a prophylactic role in arthroplasty. Arthroplasties alleviate pain while restoring joint function and improving quality of life1-3. While the number of patients undergoing total joint arthroplasty exceeds 1 million per year in the U.S.2, a serious complication of this procedure is the occurrence of a PJI, which erodes the surrounding soft tissues and bone, leading to pain, debility, and ultimately, septic implant loosening. Even though PJIs are not common, their impact on patients, surgeons, and the entire health-care system is enormous. Moreover, PJI remains one of the most commons reasons for early and late failure of total joint arthroplasty. As such, substantial efforts by many have focused on not only treating PJIs but also preventing them. Some epidemiological studies have indicated that most patients undergoing total joint arthroplasty are vitamin-D deficient, and vitamin-D status may correlate with PJI4,5. The epidemiological observations may be directly linked to the well-established fact that vitamin D is necessary for normal macrophage activity and inflammatory responses6. This mechanistic connection was tested by the current authors using a surgical model of PJI in which mice received a stainless-steel implant in the knee joint, followed by inoculation of the joint space with Staphylococcus aureus. Two groups of mice were fed either a vitamin-D3 sufficient or deficient diet. Within the deficient cohort, a group of mice were “rescued” by 25D3 administration prior to surgery. The results essentially showed that vitamin 25D3 rescue treatment reduced bacterial burden and neutrophil infiltration by increasing the macrophage activity, as hypothesized. Therefore, the authors postulated that, if vitamin 25D3 reduces bacterial burden, 25D deficiency may be a modifiable risk factors in the setting of PJI. The authors justifiably arrived at the modestly stated conclusion that 25D deficiency is a modifiable risk factor on the basis of their high-quality work and the candid acknowledgment of the technical limitations of working with mice. It remains to be established whether the beneficial effects of vitamin D will be observed in larger animal models or are translatable to patients. It is also important to note that decreasing bacterial burden through a number of important precautions in the operating theater does not necessarily decrease PJIs. However, the mouse data are intriguing and conceptually provocative, as this study makes a step toward a simple potential remedy—vitamin D supplementation—to reduce PJIs. Since vitamin D is relatively harmless if not useful, this potential strategy could be distinctly “low risk and high reward.”

Plasmatic Soluble Receptor for Advanced Glycation End Products as a New Oxidative Stress Biomarker in Patients with Prosthetic-Joint-Associated Infections?

Prosthetic joint infection (PJI) is the most common cause of failure of total joint arthroplasty, but a gold standard for PJI diagnosis is still lacking. Advanced glycation end products (AGEs) are proinflammatory molecules inducing intracellular oxidative stress (OS) after binding to their cell membrane receptors (RAGE). The aim of this study was to evaluate plasmatic soluble receptor for advanced glycation end products (sRAGE), as a new OS and infection marker correlating sRAGE to the level of OS and antioxidant defenses, in PJI, in order to explore the possible application of this new biomarker in the early diagnosis of PJI. Plasmatic sRAGE levels (by ELISA assay), plasma antioxidant total defenses (by lag time method), plasma reactive oxygen species (ROS), and thiobarbituric acid reactive substance (TBARS) levels (by colorimetric assay) were evaluated in 11 PJI patients and in 30 matched controls. ROS and TBARS were significantly higher (p < 0.001) while plasma total antioxidant capacity and sRAGE were significantly lower (p < 0.01) in patients with PJI compared to controls. Our results confirm the OS in PJI and show a strong negative correlation between the level of sRAGE and oxidative status, suggesting the plasmatic sRAGE as a potential marker for improving PJI early diagnosis.

Triple prophylaxis for the prevention of surgical site infections in total joint arthroplasty

Background: Surgical site infection is a devastating complication and the most common mode of failure in total joint arthroplasty (TJA). The purpose of this study was to evaluate a unique triple prophylaxis protocol (preoperative nasal application of mupirocin, preoperative intravenous administration of vancomycin, and intraoperative betadine irrigation) in reducing surgical site infection rates in TJA. Methods: Our sample included 1034 consecutive patients who underwent primary hip or knee TJA for degenerative joint disease in the 2 yr prior to (control group) and 2 yr after institution of this protocol (treatment group). After follow-up of a minimum of 1 yr, we identified all patients who developed surgical site infection. We then calculated and compared the overall, superficial, deep, and methacillin-resistant Staphylococcus aureus (MRSA) surgical site infection rates between the control and treatment groups. Results: The overall surgical site infection rate decreased from 2.0% in our control cohort to 0.7% (P=0.08) in our treatment cohort. Rates of deep surgical site infection significantly decreased from 1.4% to 0.2% (P=0.02), but no change was observed in rates of superficial surgical site infection (0.6% to 0.6%, P=0.92). The rate of MRSA infection decreased from 0.6% to 0.2%, but this was not significant (P=0.28). Conclusions: We discovered that using this three-pronged prophylaxis approach for primary total knee and hip arthroplasties significantly decreased the rates of deep SSI compared to patients who did not receive these interventions. This protocol has the potential for changing the current protocol for preventing surgical site infection in future TJA.

Role of Toll like receptors and inflammasome in aseptic loosening

Aseptic loosening, ascribes to particle induced osteolysis, is the most common reason for total joint arthroplasty failure. Wear particles, liberated from the surface of prostheses, mediate the expression of inflammatory cytokines in macrophages and increase the osteoclastogenesis. However, it remains unclear how macrophages can recognize wear particles and be induced by wear particles. Recently, a number of studies have demonstrated that Toll like receptors and inflammasome may play a critical role in osteolysis. However, the mechanism of activation of Toll like receptors and the relationship between TLR pathway and downstream signaling pathways still remain unclear. It will be beneficial to understand the pathogenesis of aseptic loosening by exploring these mechanisms. This article highlights the role of Toll like receptors and inflammasome in aseptic loosening, which is helpful to the development of therapies that prevent wear particle induced aseptic loosening.

Autophagy mediated TiAl6V4 particle-induced peri-implant osteolysis by promoting expression of TNF-α

Peri-prosthetic osteolysis and the consequent aseptic loosening constitute the most common reason for total joint arthroplasty failure and surgical revision. Although numerous studies suggest that pro-inflammatory cytokines induced by wear particles is involved in the pathological process of aseptic loosening, the underlying mechanism linking wear particles to pro-inflammatory cytokines remains to be illustrated. In the present study, we investigated the effect of autophagy on TNF-α secretion induced by TiAl6V4 particles (TiPs) in macrophages and in a calvarial resorption animal model. Our study demonstrated that TiPs activated autophage in macrophages and particle-induced osteolysis animal models as well as periprosthetic membranes of patients with aseptic loosening. The autophagy inhibitor 3-MA (3-methyladenine) could dramatically reduce TiPs-induced TNF-α expression both in macrophages and in membranes from animal models. Furthermore, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Collectively, these results suggest that autophagy plays a key role in TiPs-induced osteolysis by promoting TNF-α expression and that blocking autophagy may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis.

Tribological characterization of zirconia coatings deposited on Ti6Al4V components for orthopedic applications

One of the most important issues leading to the failure of total joint arthroplasty is related to the wear of the plastic components, which are generally made of ultra high molecular weight polyethylene (UHMWPE). Therefore, the reduction of joint wear represents one of the main challenges the research in orthopedics is called to address nowadays. Surface treatments and coatings have been recognized as innovative methods to improve tribological properties, also in the orthopedic field.This work investigated the possibility to realize hard ceramic coatings on the metal component of a prosthesis, by means of Pulsed Plasma Deposition, in order to reduce friction and wear in the standard coupling against UHMWPE.Ti6Al4V substrates were coated with a 2μm thick yttria-stabilized zirconia (YSZ) layer. The mechanical properties of the YSZ coatings were assessed by nanoindentation tests performed on flat Ti6Al4V substrates. Tribological performance was evaluated using a ball-on-disk tribometer in dry and lubricated (i.e. with fetal bovine serum) highly-stressing conditions, up to an overall distance of 10km. Tribology was characterized in terms of coefficient of friction (CoF) and wear rate of the UHMWPE disk. After testing, specimens were analyzed through optical microscopy and SEM images, in order to check the wear degradation mechanisms. Progressive loading scratch tests were also performed in dry and wet conditions to determine the effects of the environment on the adhesion of the coating.Our results supported the beneficial effect of YSZ coating on metal components. In particular, the proposed solution significantly reduced UHMWPE wear rate and friction. At 10km of sliding distance, a wear rate reduction of about 18% in dry configuration and of 4% in presence of serum, was obtained by the coated group compared to the uncoated group. As far as friction in dry condition is concerned, the coating allowed to maintain low CoF values until the end of the tests, with an overall difference of about 40% compared to the uncoated balls. In wet conditions, the friction values were found to be comparable between coated and uncoated materials, mainly due to a premature delamination of the coating. Scratch tests in wet showed in fact a reduction of the critical load required to a complete delamination due to a formation of blister, although no change or damage occurred at the coating during the soaking period.Although conditions of high values of contact pressure were considered, further analyses are however required to fully understand the behavior of YSZ coatings in wet environment and additional research on the deposition process will be mandatory in order to improve the coating tribological performance at long distances addressing orthopedic applications.

Genetic susceptibility to prosthetic joint infection following total joint arthroplasty: A systematic review

BackgroundProsthetic joint infection (PJI) is the most common cause of total joint arthroplasty failure and revision surgery. Genetic polymorphisms could be determinant factors for PJI. MethodsWe performed a systematic research of Medline, Pubmed, Embase, Cochrane Library, and Google Scholar, and identified 11 studies with 34 kinds of gene polymorphisms, were included in the synthesis. ResultsOur data suggest that the C allele and genotype C/C for MBL-550 SNP, genotype A/A for MBL-54 SNP and G allele for MBL-221 SNP increase the risk of PJI, while G allele and genotype G/G for MBL-550 SNP decrease the risk of PJI in Caucasian populations. Several other genes reported by single-center studies also contribute to the genetic susceptibility to septic PJI. No definitive conclusions could be achieved due to the small amount of data in the included studies. ConclusionSeveral genes contribute to the genetic susceptibility to PJI following total joint arthroplasty. Further studies will enhance the understanding of PJI, and may inform and direct early interventions.

Soluble urokinase-type plasminogen activator receptor (suPAR) as new biomarker of the prosthetic joint infection: Correlation with inflammatory cytokines

Post-operative prosthetic joint infection (PJI) is the most common cause of failure of total joint arthroplasty, requiring revision surgery, but a gold standard for the diagnosis and the treatment of PIJ is still lacking. PJI is mainly due to Gram-positive bacteria, in particular, Staphylococcus Aureus, and more rarely by Gram-negative bacteria such as Pseudomonas. This study aimed to examine the diagnostic value of SuPAR in post-operative PJI, in order to explore the possible application of this new biomarker in the early diagnosis of PJI. The level of SuPAR has been measured in PJI patients and healthy controls, correlated with canonical inflammatory markers, such as C-reactive protein, IL-6, IL-1 and TNFα and the chemokine CCL2. Serum suPAR displayed a strongly significative increase in PJI patients compared to not infected controls, and a significative positive correlation with C-reactive protein, IL-6, IL-1 and TNFα and the chemokine CCL2. Also serum CCL2 showed statistically significative increase in PJI patients, and it displayed a strong positive correlation with serum suPAR. This study provides a clear indication of the diagnostic potential of suPAR, in association to routine inflammatory parameters such as CRP, in the diagnosis of PJI.

Adenovirus-mediated siRNA targeting TNF-α and overexpression of bone morphogenetic protein-2 promotes early osteoblast differentiation on a cell model of Ti particle-induced inflammatory response in vitro

Wear particles are phagocytosed by macrophages and other inflammatory cells, resulting in cellular activation and release of proinflammatory factors, which cause periprosthetic osteolysis and subsequent aseptic loosening, the most common causes of total joint arthroplasty failure. During this pathological process, tumor necrosis factor-alpha (TNF-α) plays an important role in wear-particle-induced osteolysis. In this study, recombination adenovirus (Ad) vectors carrying both target genes [TNF-α small interfering RNA (TNF-α-siRNA) and bone morphogenetic protein 2 (BMP-2)] were synthesized and transfected into RAW264.7 macrophages and pro-osteoblastic MC3T3-E1 cells, respectively. The target gene BMP-2, expressed on pro-osteoblastic MC3T3-E1 cells and silenced by the TNF-α gene on cells, was treated with titanium (Ti) particles that were assessed by real-time PCR and Western blot. We showed that recombinant adenovirus (Ad-siTNFα-BMP-2) can induce osteoblast differentiation when treated with conditioned medium (CM) containing RAW264.7 macrophages challenged with a combination of Ti particles and Ad-siTNFα-BMP-2 (Ti-ad CM) assessed by alkaline phosphatase activity. The receptor activator of nuclear factor-κB ligand was downregulated in pro-osteoblastic MC3T3-E1 cells treated with Ti-ad CM in comparison with conditioned medium of RAW264.7 macrophages challenged with Ti particles (Ti CM). We suggest that Ad-siTNFα-BMP-2 induced osteoblast differentiation and inhibited osteoclastogenesis on a cell model of a Ti particle-induced inflammatory response, which may provide a novel approach for the treatment of periprosthetic osteolysis.

Substance P enhanced titanium particles-induced RANKL expression in fibroblasts from periprosthetic membrane

Aseptic loosening remains the primary cause of failure in total joint arthroplasty. Implant-derived particles are thought to be a main cause of osteolysis that leads to the failure. Substance P (SP) immunoreactive nerve fibers have been detected in the periprosthetic membrane of aseptic loose hip prostheses. We isolated fibroblasts from periprosthetic membrane. Fibroblasts were examined by real-time RT-PCR and enzyme-linked immunosorbent assay for expression of the receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), cyclooxygenase (COX)-1, and COX-2. Experiments were performed in the presence and absence of titanium particles, SP and NS-398 (a selective COX-2 inhibitor). Titanium particles or SP stimulated RANKL and COX-2 expression in fibroblasts, whereas NS-398 inhibited RANKL production, suggesting a COX-2-mediated event. Moreover, SP enhanced COX-2 and RANKL expression by titanium particles-stimulated fibroblasts. Thus, SP and titanium particles acted synergistically to increase RANKL expression.

Biochemical markers in total joint arthroplasty: electrophoresis of joint fluid proteins as a new diagnostic tool for prosthetic performance

Despite the advances in prosthetic materials and surgical procedures, osteolysis and aseptic loosening are the most common cause of orthopedic implant failure in total joint arthroplasty. Because of risk factors diversity and complexity of cellular and biochemical mechanisms of osteolysis, the challenge is to identify new biochemical markers, more specific and sensitive, for early detection of biochemical changes in joint fluid and screening of patient with high risk for aseptic loosening. Current systemic markers of implant wear include markers of bone turnover (propeptides and telopeptides of collagen) and inflammatory reactions (interleukins), as well as products of wear process (metal ions). The multitude of interferences, the great amounts of biological fluid necessary for analysis, and the viscosity of joint fluid limit their clinical value. Electrophoresis of joint fluid proteins using Hyrys-Hydrasys SEBIA France system enriches the panel of biochemical tests available for assessment of aseptic loosening. The multitude of proteins that can be separated using a small quantity of joint fluid with minor interferences is the main advantage of this investigation technique. The electrophoretic biomarkers as well as their diagnostic and prognostic value in aseptic loosening are presented.

Genetic epidemiology of hip and knee osteoarthritis

Osteoarthritis (OA) is the most common cause of arthritis and represents an enormous healthcare burden in industrialized societies. Current therapeutic approaches for OA are limited and are insufficient to prevent the initiation and progression of the disease. Genetic studies of patients with OA can help to unravel the molecular mechanisms responsible for specific disease manifestations, including joint damage, nociception and chronic pain. Indeed, these studies have identified molecules, such as growth/differentiation factor 5, involved in signaling cascades that are important for the pathology of joint components. Genome-wide association studies have uncovered a likely role in OA for the genes encoding structural extracellular matrix components (such as DVWA) and molecules involved in prostaglandin metabolism (such as DQB1 and BTNL2). A ∼300 kilobase region in chromosome 7q22 is also associated with OA susceptibility. Finally, the identification of individuals at a high risk of OA and of total joint arthroplasty failure might be facilitated by the use of combinations of genetic markers, allowing for the application of preventive and disease-management strategies.

The clinical relevance of genetic susceptibility to osteoarthritis

Osteoarthritis is a major musculoskeletal cause of disability in the elderly, but current therapeutic approaches are insufficient to prevent initiation and progression of the disease. Genetic studies in humans have identified molecules involved in signalling cascades that are important for the pathology of the joint components. These include the bone morphogenetic protein (BMP) signalling, the wingless-type signalling and the thyroid pathway as well as apoptotic-related molecules. There is emerging evidence indicating that inflammatory molecules related to cytokine production, prostaglandin and arachidonic acid metabolism are also involved in susceptibility to osteoarthritis. All of these pathways are likely targets for pharmacological intervention. Genetic variation also affects pain due to osteoarthritis highlighting molecular mechanisms for pain relief. Moreover, combinations of genetic markers can be used to identify individuals at high risk of osteoarthritis and risk of total joint arthroplasty failure, which should facilitate the application of preventive and disease management strategies.