The Relationship Between Intra-articular Fracture Energy and a Patient's Inflammatory Response.

OBJECTIVES: Prior studies have demonstrated elevated inflammatory cytokine concentrations in the synovial fluid of articular fracture patients postinjury. Similarly, CT-based fracture energy measurements have been correlated with posttraumatic osteoarthritis risk after pilon fracture. The purpose of this study was to determine the associations between synovial fluid cytokine levels, fracture energy, and overall trauma to the body in articular fracture patients. METHODS: Acute tibial plateau, tibial plafond, and rotational ankle fracture patients were prospectively enrolled from December 2011 through January 1, 2019. Synovial fluid concentrations of interleukin-1 beta, interleukin-1 receptor antagonist, IL-6, IL-8, IL-10, matrix metallopeptidase-1, MMP-3, and MMP-13 were quantified. Patient CT scans were used to calculate fracture energy. The Injury Severity Score (ISS) was used to relate cytokine levels to whole-body injury severity. Spearman rho correlation coefficients were calculated to assess the relationship between injury severity metrics and synovial fluid cytokine, chemokine, and matrix metallopeptidase concentrations. RESULTS: Eighty-seven patients were enrolled with 42 had a tibial plateau fractures (OTA/AO 41B1-2, 41B2-14, 41B3-3, 41C1-3, 41C2-4, 41C3-16), 24 patients had a tibial plafond fracture (OTA/AO 43B1-2, 43B2-4, 43B3-5, 43C1-2, 43C2-3, 43C3-8), and 21 had a rotational ankle fracture (OTA/AO 44B1-3, 44B2-3, 44B3-6, 44C1-4, 44C2-5). Fracture energy significantly differed between fracture patterns, with ankle fractures involving substantially less fracture energy (median = 2.92 J) than plafond (10.85 J, P < 0.001) and plateau fractures (13.05 J, P < 0.001). After adjustment for multiple comparisons, MMP-3 was significantly correlated with transformed fracture energy (r = 0.41, 95% confidence interval [CI], 0.22-0.58, P < 0.001), while IL-1ß was significantly correlated with the Injury Severity Score (Spearman ρ = 0.31, 95% CI, 0.08-0.49, P = 0.004). CONCLUSIONS: Synovial fluid MMP-3 concentration was significantly correlated with CT-quantified fracture energy in intra-articular fracture patients. Given that in clinical practice fracture energy tends to correlate with posttraumatic osteoarthritis risk, MMP-3 may warrant further investigation for its role in posttraumatic osteoarthritis development after articular fracture. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Elevation of Pro-Inflammatory Cytokine Levels Following Intra-Articular Fractures-A Systematic Review.

Introduction: Intra-articular fractures are a major cause of post-traumatic osteoarthritis (PTOA). Despite adequate surgical treatment, the long-term risk for PTOA is high. Previous studies reported that joint injuries initiate an inflammatory cascade characterized by an elevation of synovial pro-inflammatory cytokines, which can lead to cartilage degradation and PTOA development. This review summarizes the literature on the post-injury regulation of pro-inflammatory cytokines and the markers of cartilage destruction in patients suffering from intra-articular fractures. Methods: We searched Medline, Embase, and Cochrane databases (1960-February 2020) and included studies that were performed on human participants, and we included control groups. Two investigators assessed the quality of the included studies using Covidence and the Newcastle-Ottawa Scale. Results: Based on the surveyed literature, several synovial pro-inflammatory cytokines, including interleukins (IL)-1ß, IL-2, IL-6, IL-8, IL-12p70, interferon-y, and tumor necrosis factor-α, were significantly elevated in patients suffering from intra-articular fractures compared to the control groups. A simultaneous elevation of anti-inflammatory cytokines such as IL-10 and IL-1RA was also observed. In contrast, IL-13, CTX-II, and aggrecan concentrations did not differ significantly between the compared cohorts. Conclusions: Overall, intra-articular fractures are associated with an increase in inflammation-related synovial cytokines. However, more standardized studies which focus on the ratio of pro- and anti-inflammatory cytokines at different time points are needed.

Cartilage Trauma Induces Necroptotic Chondrocyte Death and Expulsion of Cellular Contents.

Necroptotic cell death is characterized by an activation of RIPK3 and MLKL that leads to plasma membrane permeabilization and the release of immunostimulatory cellular contents. High levels of chondrocyte death occur following intra-articular trauma, which frequently leads to post-traumatic osteoarthritis development. The aim of this study is to assess necroptosis levels in cartilage post-trauma and to examine whether chondrocyte necroptotic mechanisms may be investigated and modified in vitro. Fractured human and murine cartilage, analysed immunohistochemically for necroptosis marker expression, demonstrated significantly higher levels of RIPK3 and phospho-MLKL than uninjured controls. Primary murine chondrocytes stimulated in vitro with the TNFα and AKT-inhibitor alongside the pan-caspase inhibitor Z-VAD-fmk exhibited a significant loss of metabolic activity and viability, accompanied by an increase in MLKL phosphorylation, which was rescued by further treatment of chondrocytes with necrostatin-1. Transmission electron microscopy demonstrated morphological features of necroptosis in chondrocytes following TNFα and Z-VAD-fmk treatment. Release of dsDNA from necroptotic chondrocytes was found to be significantly increased compared to controls. This study demonstrates that cartilage trauma leads to a high prevalence of necroptotic chondrocyte death, which can be induced and inhibited in vitro, indicating that both necroptosis and its consequential release of immunostimulatory cellular contents are potential therapeutic targets in post-traumatic arthritis treatment.

Inflammatory cytokines and matrix metalloproteinases in the synovial fluid after intra-articular elbow fracture.

BACKGROUND AND HYPOTHESIS: Post-traumatic elbow contracture remains a common and challenging complication with often unsatisfactory outcomes. Although the etiology is unknown, elevated or abnormal post-fracture synovial fluid cytokine levels may result in the migration of fibroblasts to the capsule and contribute to capsular pathology. Thus, the purpose of this study was to characterize the cytokine composition in the synovial fluid fracture hematoma of patients with intra-articular elbow fractures. METHODS: The elbow synovial fluid fracture hematoma of 11 patients with intra-articular elbow fractures was analyzed for CTXII (C-terminal telopeptides of type II collagen [a cartilage breakdown product]) as well as 15 cytokines and matrix metalloproteinases (MMPs) including interferon γ, interleukin (IL) 1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor α, MMP-1, MMP-2, MMP-3, MMP-9, and MMP-10. The uninjured, contralateral elbow served as a matched control. Mean concentrations of each factor were compared between the fluid from fractured elbows and the fluid from control elbows. RESULTS: The levels of 14 of 15 measured cytokines and MMPs-interferon γ, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor α, MMP-1, MMP-3, MMP-9, and MMP-10-were significantly higher in the fractured elbows. In addition, post hoc power analysis revealed that 10 of 14 significant differences were detected with greater than 90% power. The mean concentration of CTXII was not significantly different between groups. CONCLUSIONS: These results demonstrate a proinflammatory environment after fracture that may be the catalyst to the development of post-traumatic elbow joint contracture. The cytokines with elevated levels were similar, although not identical, to the cytokines with elevated levels in studies of other weight-bearing joints, indicating the elbow responds uniquely to trauma.

Laboratory Monitoring of Bone Tissue Remodeling after Augmentation of Impression Intraarticular Fracture with Different Types of Bone Graft.

The effects of bone graft materials on the inflammatory response and biochemical markers of bone remodeling were studied on a rabbit model of fracture augmentation with the following grafts: ß-tricalcium phosphate, demineralized bone matrix, nanostructured carbon implant, and porous titanium implant made by additive 3D printing. The markers of bone remodeling and the blood system response in the postoperative period were studied. It was found that porous titanium implant and ß-tricalcium phosphate induced osteogenesis and minimized osteoclastic resorption. Augmentation with nanostructured carbon implant and demineralized bone matrix stimulated the processes of osteoclastic resorption.

Amino Acid Profile of Synovial Fluid Following Intra-articular Ankle Fracture.

BACKGROUND: Post-traumatic osteoarthritis (PTOA) is a frequent complication in patients with a previous traumatic joint injury, and the pathophysiology is not well understood. The goal of this study was to characterize the biochemical signature of amino acids, peptides, and amino acid metabolites in ankle synovial fluid following intra-articular fracture. METHODS: Synovial fluid from both the injured and contralateral ankles of 19 patients with an intra-articular ankle fracture was obtained and analyzed via metabolic profiling. Follow-up analysis was performed after 6 months in 7 of these patients. RESULTS: Statistical comparisons between injured and contralateral ankles revealed that 19 of the 66 measured amino acids, peptides, and amino acid metabolites were significantly elevated at time of fracture. Metabolites associated with glutathione metabolism exhibited the most elevated mean-fold changes, indicating a possible role for oxidative stress in fractured ankles. None of the metabolites elevated at baseline were significantly elevated after 6 months, but 6 metabolites had mean-fold changes greater than 2.1 at this time point. Multiple metabolites also exhibited significant correlations ( r > 0.575) with matrix metalloproteinase-1 and -9. CONCLUSION: These results indicate the presence of amino acid metabolic products in the setting of ankle fracture and suggest that these changes in amino acid metabolism may be chronic and indicate a role for inflammation and collagen degradation in disease progression. CLINICAL RELEVANCE: Changes in amino acid metabolism following intra-articular fracture may contribute to the progression to PTOA. This knowledge may allow for the identification and early treatment of patients at risk of developing PTOA. LEVEL OF EVIDENCE: Level III, comparative series.

Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis.

We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA.

Time-Dependent Effects on Synovial Fluid Composition During the Acute Phase of Human Intra-articular Ankle Fracture.

BACKGROUND: The study objective was to examine the effect of time and fracture severity on the undiluted synovial fluid (SF) microenvironment during the acute phase following intra-articular fracture (IAF) of the human ankle. METHODS: Ankle SF from 54 patients with an acute IAF was analyzed for concentrations of 10 cytokines, 5 matrix metalloproteinases, 2 products of cartilage catabolism, and combined products of heme metabolism. All analytes were correlated with time from fracture and further analyzed for an effect of 3 time subgroups (0-2 days, 3-9 days, and ≥10 days) corresponding to timepoints for clinical ankle fracture interventions. The effect of fracture severity was determined by grouping SF according to the number of radiographic intra-articular fracture lines. RESULTS: Fifteen of 18 analytes were significantly correlated with time. Temporal grouping of SF revealed an initial (0-2 days) spike of pro-inflammatory (IL-12p70, IL-1ß, IL-6) and anti-inflammatory (IL-10 and IL-4) cytokines, matrix metalloproteinases (MMP) MMP-9, and sGAG, followed immediately (3-9 days) by products of heme metabolism and an unchallenged surge in mediators and products of cartilage catabolism (MMP-1, MMP-2, MMP-3, MMP-10, and CTX-II). After 10 days, there was a decrease in pro- and anti-inflammatory cytokines but a persistence of mediators of ECM catabolism. There was no clear relationship between the number of fracture lines and SF levels of analytes. CONCLUSIONS: This study demonstrated acute temporal fluctuations following ankle IAF resulting in an overall catabolic environment by 10 days post-fracture and supports consideration of an early evacuation of the joint space to reduce the intra-articular inflammatory burden. Clinical Relavence: This study contributes to the understanding of the intra-articular events that potentially contribute to the development of posttraumatic osteoarthritis acutely following IAF in the ankle.

Inflammatory Cytokines and Matrix Metalloproteinases in the Synovial Fluid After Intra-articular Ankle Fracture.

BACKGROUND: Posttraumatic osteoarthritis (PTOA) can occur after intra-articular fracture despite anatomic fracture reduction. It has been hypothesized that an early inflammatory response after intra-articular injury could lead to irreversible cartilage damage that progresses to PTOA. Therefore, in addition to meticulous fracture reduction, it would be ideal to prevent this initial inflammatory response but little is known about the composition of the synovial environment after intra-articular fracture. The purpose of this work was to characterize the inflammatory cytokine and matrix metalloproteinase (MMP) composition in the synovial fluid (SF) of patients with acute intra-articular ankle fractures. METHODS: Twenty-one patients with an intra-articular ankle fracture were included in this study. All patients had a contralateral ankle joint that was pain free, had no radiographic evidence of arthritis, and no history of trauma. The uninjured ankle served as a matched control. SF was obtained from bilateral ankles at the time of surgery which occurred at a mean of 17 days post-fracture (range 8-40). The SF was analyzed for granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p70, MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, CTXII, sGAG, and bilirubin/biliverdin (markers of hemearthrosis) using either multiplex assay or ELISA using commercially available kits. Mean concentrations of each factor were compared between SF from fractured and control ankles, and correlation analysis was done to determine potential relationships between levels of cytokines and time from fracture and age at fracture. RESULTS: Twelve of 18 measured factors including GM-CSF, IL-10, IL-1ß, IL-6, IL-8, TNF-α, MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, and bilirubin/biliverdin were found to be significantly higher in the fractured ankles. Mean concentrations of ECM degradation markers (sGAG and CTXII) were not found to be significatnly different between groups. CONCLUSION: These data indicate that after intra-articular ankle fracture the SF exhibits a largely pro-inflammatory and extra-cellular matrix degrading environment similar to that described in idiopathic osteoarthritis. IL-6, IL-8, MMP-1, MMP-2, MMP-3, MMP-9, and MMP-10 were significantly elevated and may play a role in the development of PTOA. CLINICAL RELEVANCE: In addition to anatomic fracture reduction, these data lend credence to reducing acute intra-articular inflammation through the development of antagonists to these pro-inflammatory and degrading mediators. Likewise, intra-articular lavage might reduce this inflammatory burden.

Intraarticular Matrix Metalloproteinases and Aggrecan Degradation Are Elevated After Articular Fracture.

BACKGROUND: Posttraumatic osteoarthritis (OA) is a variant of OA that can develop after articular injury. Although the mechanism(s) of posttraumatic OA are uncertain, the presence and impact of postinjury proteolytic enzymes on articular cartilage remain unknown. To our knowledge, there are no studies that evaluate the presence of matrix metalloproteinases (MMPs) or aggrecan degradation after articular fracture. QUESTIONS/PURPOSES: (1) Are MMP concentrations and aggrecan degradation elevated after intraarticular fracture? (2) Are MMP concentrations and aggrecan degradation greater in high-energy injuries compared with low-energy injuries? (3) Do the concentrations of these biomarkers remain elevated at a secondary aspiration? METHODS: Between December 2011 and June 2013, we prospectively enrolled patients older than 18 years of age with acute tibial plateau fracture. Exclusion criteria included age older than 60 years, preexisting knee OA, injury greater than 24 hours before evaluation, contralateral knee injury, history of autoimmune disease, open fracture, and non-English-speaking patients. During the enrollment period, we enrolled 45 of the 91 (49%) tibial plateau fractures treated at our facility. Knee synovial fluid aspirations were obtained from both the injured and uninjured knees; two patients received aspirations in the emergency department and the remaining patients received aspirations in the operating room. Twenty patients who underwent spanning external fixator followed by definitive fixation were aspirated during both surgical procedures. MMP-1, -2, -3, -7, -9, -10, -12, and -13 concentrations were quantified using multiplex assays. Aggrecan degradation was quantified using sandwich enzyme-linked immunosorbent assay. RESULTS: There were higher concentrations of MMP-1 (3.89 ng/mL [95% confidence interval {CI}, 2.37-6.37] versus 0.37 ng/mL [95% CI, 0.23-0.61], p < 0.001), MMP-3 (457.35 ng/mL [95% CI, 274.5-762.01] versus 129.17 ng/mL [95% CI, 77.01-216.66], p < 0.001), MMP-9 (6.52 ng/mL [95% CI, 3.86-11.03] versus 0.96 ng/mL [95% CI, 0.56-1.64], p < 0.001), MMP-10 (0.52 ng/mL [95% CI, 0.40-0.69] versus 0.23 ng/mL [95% CI, 0.17-0.30], p < 0.001), and MMP-12 (0.18 ng/mL [95% CI, 0.14-0.23] versus 0.10 ng/mL [95% CI, 0.0.081-0.14], p = 0.005) in injured knees compared with uninjured knees. There was not a detectable difference in MMP concentrations or aggrecan degradation between high- and low-energy injuries. MMP-1 (53.25 versus 3.89 ng/mL, p < 0.001), MMP-2 (76.04 versus 0.37 ng/mL, p < 0.001), MMP-3 (1250.62 versus 457.35 ng/mL, p = 0.002), MMP-12 (1.37 versus 0.18, p < 0.001), MMP-13 (0.98 versus 0.032 ng/mL, p < 0.001), and aggrecan degradation (0.58 versus 0.053, p < 0.001) were increased at the second procedure (mean, 9.5 days; range, 3-21 days) as compared with the initial procedure. CONCLUSIONS: Because MMPs and aggrecan degradation are elevated after articular fracture, future studies are necessary to evaluate the impact of elevated MMPs and aggrecan degradation on human articular cartilage. CLINICAL RELEVANCE: If further clinical followup can demonstrate a relationship between posttraumatic OA and elevated MMPs and aggrecan degradation, they may provide potential for therapeutic targets to prevent or delay the destruction of the joint. Additionally, these markers may offer prognostic information for patients.

Does intra-articular fracture change the lubricant content of synovial fluid?

BACKGROUND: Lubrication function is impaired and the lubricant content of synovial fluid (SF) changes immediately after plateau tibia fractures. Here, we aimed to analyze the lubricant content of SF at chronic term following plateau tibia fracture. METHODS: Forty-eight surgically treated patients without joint incongruency (<2 mm displacement) were included in the study. Joint aspiration had been possible in 16 of the participants. However, sampling could be made from healthy knees in only ten of these patients. Twenty-six SF samples (16 injured knees, 10 healthy knees) were analyzed for concentrations of hyaluronic acid (HA), proteoglycan-4 (PRG4), TNF-α, IL-1ß, and IL-6. RESULTS: The group of experimental samples were obtained at a mean of 31 (12-66) months after injury from patients with a mean age of 45.1 (32-57) years. There were no relationships detected between biochemical analysis results and patient ages, sexes, postoperative time, and fracture type. After excluding six patients for whom we could not sample from their healthy knee, ten patients' values were compared with paired Wilcoxon signed rank test and no significant differences detected between the healthy and injured knee in terms of the SF concentrations of HA and PRG4 (p = 0.225 and 0.893, respectively). Similarly, there were no statistically significant differences in SF sample concentrations of TNF-α, IL-1ß, and IL-6 between healthy and injured knees. CONCLUSIONS: Despite acute changes, the long-term concentrations of HA and PRG4 were similar after plateau tibial fracture. We could not detect any concentration level differences between healthy knees and injured knees regarding HA and PRG4 in the long-term follow-up.

Inflammatory cytokine response following acute tibial plateau fracture.

BACKGROUND: The objective of the present study was to evaluate human synovial fluid for inflammatory cytokine concentrations following acute tibial plateau fracture. Our hypothesis was that there would be an elevated inflammatory response following intra-articular fracture, and that the inflammatory response would be greater after high-energy compared with low-energy injuries. METHODS: Between December 2011 and June 2013, we prospectively enrolled forty-five patients with an acute tibial plateau fracture. Synovial fluid aspirations were performed on the injured and uninjured knees. Twenty patients who required an external fixator followed by delayed fixation underwent aspiration at both surgical procedures. The concentrations of interferon-gamma (IFN-γ), interleukin-1 beta (IL-1ß), interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1ß) were quantified with use of multiplex assays. RESULTS: The forty-five patients had an average age of forty-two years (range, twenty to sixty years). There were twenty-four low-energy and twenty-one high-energy tibial plateau injuries. There was a significant difference between injured and uninjured knees (p < 0.001) with regard to concentrations of IL-1ß, IL-6, IL-8, IL-10, IL-1RA, and MCP-1. There was not a detectable difference in synovial fluid cytokine concentrations between high and low-energy injuries. The concentrations of IL-10 (p < 0.001), IL-1RA (p = 0.002), IL-6 (p < 0.001), IL-8 (p < 0.001), and MCP-1 (p = 0.002) were significantly greater in the injured knee than in the uninjured knee at the second aspiration, at a mean of 9.5 days (range, three to twenty-one days) after the initial injury. CONCLUSIONS: There was a significant local inflammatory response following acute tibial plateau fracture. There was not a detectable difference in inflammatory cytokine concentration between high and low-energy injuries. Synovial fluid concentrations of IL-10, IL-8, IL-6, IL-1RA, and MCP-1 remained elevated at the second aspiration.

Effect of tibial plateau fracture on lubrication function and composition of synovial fluid.

BACKGROUND: Intra-articular fractures may hasten posttraumatic arthritis in patients who are typically too active and too young for joint replacement. Current orthopaedic treatment principles, including recreating anatomic alignment and establishing articular congruity, have not eliminated posttraumatic arthritis. Additional biomechanical and biological factors may contribute to the development of arthritis. The objective of the present study was to evaluate human synovial fluid for friction-lowering function and the concentrations of putative lubricant molecules following tibial plateau fractures. METHODS: Synovial fluid specimens were obtained from the knees of eight patients (twenty-five to fifty-seven years old) with a tibial plateau fracture, with five specimens from the injured knee as plateau fracture synovial fluid and six specimens from the contralateral knee as control synovial fluid. Each specimen was centrifuged to obtain a fluid sample, separated from a cell pellet, for further analysis. For each fluid sample, the start-up (static) and steady-state (kinetic) friction coefficients in the boundary mode of lubrication were determined from a cartilage-on-cartilage biomechanical test of friction. Also, concentrations of the putative lubricants, hyaluronan and proteoglycan-4, as well as total protein, were determined for fluid samples. RESULTS: The group of experimental samples were obtained at a mean (and standard deviation) of 11 ± 9 days after injury from patients with a mean age of 45 ± 13 years. Start-up and kinetic friction coefficients demonstrated similar trends and dependencies. The kinetic friction coefficients for human plateau fracture synovial fluid were approximately 100% higher than those for control human synovial fluid. Hyaluronan concentrations were ninefold lower for plateau fracture synovial fluid compared with the control synovial fluid, whereas proteoglycan-4 concentrations were more than twofold higher in plateau fracture synovial fluid compared with the control synovial fluid. Univariate and multivariate regression analysis indicated that kinetic friction coefficient increased as hyaluronan concentration decreased. CONCLUSIONS: Knees afflicted with a tibial plateau fracture have synovial fluid with decreased lubrication properties in association with a decreased concentration of hyaluronan.

Acute joint pathology and synovial inflammation is associated with increased intra-articular fracture severity in the mouse knee.

OBJECTIVE: Post-traumatic arthritis is a frequent cause of disability and occurs most commonly and predictably after articular fracture. The objective of this investigation was to examine the effect of fracture severity on acute joint pathology in a novel murine model of intra-articular fracture. DESIGN: Low and high energy articular fractures (n=25 per group) of the tibial plateau were created in adult male C57BL/6 mice. The acute effect of articular fracture severity on synovial inflammation, bone morphology, liberated fracture area, cartilage pathology, chondrocyte viability, and systemic cytokines and biomarkers levels was assessed at 0, 1, 3, 5, and 7 days post-fracture. RESULTS: Increasing intra-articular fracture severity was associated with greater acute pathology in the synovium and bone compared to control limbs, including increased global synovitis and reduced periarticular bone density and thickness. Applied fracture energy was significantly correlated with degree of liberated cortical bone surface area, indicating greater comminution. Serum concentrations of hyaluronic acid (HA) were significantly increased 1 day post-fracture. While articular fracture significantly reduced chondrocyte viability, there was no relationship between fracture severity and chondrocyte viability, cartilage degeneration, or systemic levels of cytokines and biomarkers. CONCLUSIONS: This study demonstrates that articular fracture is associated with a loss of chondrocyte viability and increased levels of systemic biomarkers, and that increased intra-articular fracture severity is associated with increased acute joint pathology in a variety of joint tissues, including synovial inflammation, cortical comminution, and bone morphology. Further characterization of the early events following articular fracture could aid in the treatment of post-traumatic arthritis.

Effect of different molecular weight hyaluronans on osteoarthritis-related protein production in fibroblast-like synoviocytes from patients with tibia plateau fracture.

BACKGROUND: Preventing arthritic change in a joint with an intra-articular fracture remains a challenge, especially in weight-bearing joints. Hyaluronan (HA) has been proven to be effective in relieving joint pain and improving function in chronic osteoarthritis. However, controversy still exists about its potential use in a joint with an intra-articular fracture and about whether this effect is dependent on molecular weight. We analyzed and compared the effects of two different molecular weight HAs on six osteoarthritis-related proteins expressed in fibroblast-like synoviocytes from 12 patients with tibial plateau fracture. METHODS: The interleukin (IL)-1beta-stimulated or IL-1beta-unstimulated fibroblast-like synoviocytes were cultivated with or without treatment by two different molecular weight HAs. The production of these proteins was quantified by using commercially available sandwich enzyme-linked immunosorbent assay. RESULTS: The results revealed that HA with a high molecular weight is more effective in downregulating proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha. Conversely, HA with a low molecular weight has greater efficacy in upregulating anticatabolic enzymes, such as tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2, and in suppressing the catabolic enzyme, matrix metalloproteinase-3, which are thought to be more chondroprotective. CONCLUSIONS: In a knee joint with an intra-articular fracture of the tibial plateau, we posit that high molecular weight HA may have a better anti-inflammatory effect, whereas low molecular weight HA has superior efficacy for chondroprotection.