Inflammatory Biomarker Profiling in Total Joint Arthroplasty and Its Relevance to Circulating Levels of Lubricin, a Novel Proteoglycan.

Lubricin, also known as proteoglycan 4, acts as an antiadhesive and boundary lubricant to prevent cartilage damage in healthy joints. Following injury, a decrease in synovial fluid (SF) lubricin may lead to secondary osteoarthritis (OA). Inflammatory biomarkers, such as IL-1ß and TNF-α, are also implicated in the pathophysiology of OA. Interestingly, they have been shown to suppress the expression and secretion of lubricin in SF. This study aims to compare circulating levels of inflammatory biomarkers and lubricin between total joint arthroplasty (TJA) patients and healthy individuals. Doing so may better elucidate their roles in OA and extend the understanding of inflammation as a regulator of lubricin. Deidentified plasma samples were obtained 1 day preoperatively and 1 day postoperatively from patients undergoing TJA. Utilizing biochip array technology, they were profiled for IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFN-γ, IL-1α, IL-1ß, MCP-1, EGF, and TNF-α. Circulating lubricin levels were also measured using enzyme-linked immunosorbent assay. Compared to healthy controls, IL-6, IL-8, VEGF, IL-1ß, MCP-1, EGF, and TNF-α were significantly increased pre- and postoperatively. Lubricin was significantly decreased. This may indicate that elevations in inflammatory cytokines initiate a cascade of events, leading to decreased lubricin, which places the joint at increased risk of developing OA.

Prevalence of metabolic syndrome in patients undergoing total joint arthroplasty and relevance of biomarkers.

BACKGROUND: Metabolic syndrome (MetS) is a collection of clinical conditions, including central obesity, hypertension, glucose intolerance and dyslipidemia. The long-term inflammatory and metabolic dysfunction associated with MetS may contribute to osteoarthritic processes leading up to total joint arthroplasty (TJA). The purpose of this study was to investigate levels of metabolic biomarkers and the prevalence of MetS in patients undergoing TJA. METHODS: Under IRB approval, citrated plasma samples were collected from 41 patients undergoing total hip and knee arthroplasty (THA/TKA) preoperatively and day 1 postoperatively. Control group consisted of 25 healthy human plasma samples (female and male, 18-35 years old) purchased from George King Biomedical Inc. (Overland Park, KS, USA). Samples were profiled for c-peptide, ferritin, IL-6, insulin, resistin, TNF-α, IL-1a, leptin, and PAI-1 using metabolic biochips purchased from RANDOX Co. (Antrim, Northern Ireland). NCEP/ATP III guidelines were used to evaluate which patients met MetS criteria. RESULTS: Levels of IL-6, resistin, TNF-a, IL-1a, leptin, and PAI-1 were significantly elevated in patients undergoing TJA compared to normal. C-peptide and insulin were both decreased in TJA compared to normal. No significance was found when comparing TJA to normal for ferritin. TNFα was significantly lower in TJA+MetS compared to TJA-MetS, while other biomarkers showed no difference in TJA±MetS populations. Insulin & c-peptide both showed a significant decrease in TJA-MetS compared to normal, but levels in TJA+MetS patients were not significantly different from controls. Resistin showed significant increases in TJA+MetS vs. normal, but not in TJA-MetS vs. normal. CONCLUSIONS: Overall, the differing metabolic profile seen in patients undergoing TJA suggest ongoing metabolic dysfunction. Insulin and c-peptide patterns among the different test groups hint toward a complex and dysfunctional metabolic process involved, with leptin and underlying insulin resistance playing a role. Increased resistin in TJA+MetS, but not in TJA-MetS, compared to normal, suggests that while elevated resistin levels may be associated with the osteoarthritic process, levels are further attenuated by MetS, which is highly prevalent in this population. Increased TNFα in TJA-MetS compared to TJA+MetS may be an artifact of differing sample populations or a true complication of the complex pathophysiology and medical regimen seen in patients with both OA and MetS. The lack of difference seen in the remaining biomarkers suggest that having MetS as a comorbidity does not contribute to the elevated levels seen in patients undergoing TJA.

Levels of Matrix Metalloproteinases in Arthroplasty Patients and Their Correlation With Inflammatory and Thrombotic Activation Processes.

An imbalance of matrix metalloproteinases (MMPs) and their inhibitors is thought to play a major role in the pathophysiology of joint diseases. The aim of this study is to provide additional insights into the relevance of MMP levels in arthroplasty patients in relation to inflammation and thrombosis. Deidentified plasma samples from 100 patients undergoing total hip arthroplasty or total knee arthroplasty were collected preoperatively, on postoperative day 1, and on postoperative day 3. Tissue inhibitor of MMP 4, tumor necrosis factor α (TNF-α), pro-MMP1, MMP3, MMP9, MMP13, and d-dimer were measured using enzyme-linked immunosorbent assay kits. A biochip array was used to profile interleukin (IL) 2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma, TNF-α, IL-1α, IL-1ß, monocyte chemoattractant protein 1, and endothelial growth factor (EGF) levels. The levels of MMP1, MMP9, MMP13, and TNF-α were elevated preoperatively in arthroplasty patients when compared to healthy individuals. The concentrations of MMP1 and MMP9 increased slightly in postsurgical samples. d-Dimer levels were elevated preoperatively, increased postoperatively, and started decreasing on postoperative day 3. Significant correlations between MMP9 with TNF-α, IL-6, IL-8, VEGF, and EGF were identified. Elevated preoperative MMP1, MMP9, and MMP13 concentrations suggest that they may play a role in the pathogenesis of arthritis. There is also evidence of increased coagulation activity and possible upregulation of several MMPs postsurgically. Correlation analysis indicates that MMP9 levels may potentially be related to inflammation and thrombosis in arthroplasty patients.

Perioperative Factors and Their Effect on the Fibrinolytic System in Arthroplasty Patients.

BACKGROUND: Total joint arthroplasty (TJA) patients are mostly of advanced age and with comorbidities such as increased body mass index (BMI) and impaired glucose tolerance. These factors and type of surgery may affect the fibrinolytic system. AIM: To investigate the effect of age, sex, BMI, type of surgery, and tranexamic acid (TXA) treatment on the fibrinolytic system in TJA patients. METHODS: Ninety-nine patients undergoing TJA (32 total hip arthroplasty [THA] and 67 total knee arthroplasty [TKA]) were included in this study. Blood samples were drawn at preoperative clinic appointments and on postoperative day 1. Antigenic levels of d-dimer, plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) were measured using a commercially available enzyme-linked immunosorbent assay kit. Antiplasmin activity was measured using functional method. Age, gender, hemoglobin (Hb) levels, and BMI were collected from the records. RESULTS: Preoperative d-dimer and tPA levels were positively correlated with age, whereas preoperative antiplasmin was negatively correlated with age. Body mass index was only associated with preoperative tPA levels. There was no significant difference in postoperative levels of d-dimer, PAI-1, tPA, or antiplasmin between patients treated with TXA or without TXA. Percentage change in d-dimer and tPA showed significantly lower values in patients treated with TXA compared to the nontreated group. Type of surgery did not affect the fibrinolytic markers. CONCLUSION: These results confirm that advanced age and elevated BMI positively contribute to fibrinolytic dysregulation in TJA patients, whereas TXA seems to decrease the fibrinolytic activity.

Fibrinolytic Dysregulation in Total Joint Arthroplasty Patients: Potential Clinical Implications.

BACKGROUND: The alterations of the fibrinolytic components in osteoarthritic joint disease and their postsurgical modulation are not clearly understood. Preexisting hemostatic dysfunction may lead to both thrombotic and bleeding events in these patients. AIM: To profile fibrinolytic parameters in patients undergoing total joint arthroplasty prior to and on postoperative day 1. METHODS: A total of 98 total joint arthroplasty patients were included in this study. Blood samples were drawn preoperatively and on postoperative day 1 status posttotal knee or total hip arthroplasty surgery. d-Dimer, plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) were measured using commercially available enzyme-linked immunosorbent assay kits. Antiplasmin activity was measured by using a functional method. RESULTS: Preoperative PAI-1, d-dimer, and tPA levels were significantly higher in arthroplasty patients compared to healthy controls. Preoperative antiplasmin level was lower than controls. Postoperative levels of PAI-1 and d-dimer were increased compared to preoperative values. Postoperative antiplasmin values were lower than preoperative levels. Changes in tPA was not significant. There was no correlation between preoperative PAI-1 and d-dimer levels. Pre- and postoperative percentage changes in each individual were calculated for PAI-1, d-dimer, tPA, and antiplasmin. There was a positive correlation between d-dimer and PAI-1. Negative correlations between antiplasmin and d-dimer and between antiplasmin and PAI-1 were noted. CONCLUSION: These results confirm the perturbation in the fibrinolytic system of patients undergoing total joint arthroplasty surgery. Surgical intervention may also enhance the observed changes. The alterations in the fibrinolytic system may lead to the observed hemostatic complications such as bleeding, hematoma formation, or potential need for blood transfusion.

In vivo analysis of the Notch receptor S1 cleavage.

A ligand-independent cleavage (S1) in the extracellular domain of the mammalian Notch receptor results in what is considered to be the canonical heterodimeric form of Notch on the cell surface. The in vivo consequences and significance of this cleavage on Drosophila Notch signaling remain unclear and contradictory. We determined the cleavage site in Drosophila and examined its in vivo function by a transgenic analysis of receptors that cannot be cleaved. Our results demonstrate a correlation between loss of cleavage and loss of in vivo function of the Notch receptor, supporting the notion that S1 cleavage is an in vivo mechanism of Notch signal control.