Association of Serum Biochemical Biomarker Profiles of Joint Tissue Inflammation and Cartilage Metabolism With Posttraumatic Osteoarthritis-Related Symptoms at 12 Months After ACLR.

BACKGROUND: Anterior cruciate ligament injury and anterior cruciate ligament reconstruction (ACLR) are risk factors for symptomatic posttraumatic osteoarthritis (PTOA). After ACLR, individuals demonstrate altered joint tissue metabolism indicative of increased inflammation and cartilage breakdown. Serum biomarker changes have been associated with tibiofemoral cartilage composition indicative of worse knee joint health but not with PTOA-related symptoms. PURPOSE/HYPOTHESIS: The purpose of this study was to determine associations between changes in serum biomarker profiles from the preoperative sample collection to 6 months after ACLR and clinically relevant knee PTOA symptoms at 12 months after ACLR. It was hypothesized that increases in biomarkers of inflammation, cartilage metabolism, and cartilage degradation would be associated with clinically relevant PTOA symptoms after ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Individuals undergoing primary ACLR were included (N = 30). Serum samples collected preoperatively and 6 months after ACLR were processed to measure markers indicative of changes in inflammation (ie, monocyte chemoattract protein 1 [MCP-1]) and cartilage breakdown (ie, cartilage oligomeric matrix protein [COMP], matrix metalloproteinase 3, ratio of type II collagen breakdown to type II collagen synthesis). Knee injury and Osteoarthritis Outcome Score surveys were completed at 12 months after ACLR and used to identify participants with and without clinically relevant PTOA-related symptoms. K-means cluster analyses were used to determine serum biomarker profiles. One-way analyses of variance and logistic regressions were used to assess differences in Knee injury and Osteoarthritis Outcome Score subscale scores and clinically relevant PTOA-related symptoms between biomarker profiles. RESULTS: Two profiles were identified and characterized based on decreases (profile 1: 67% female; age, 21.4 ± 5.1 years; body mass index, 24.4 ± 2.4) and increases (profile 2: 33% female; age, 21.3 ± 3.2 years; body mass index, 23.4 ± 2.6) in sMCP-1 and sCOMP preoperatively to 6 months after ACLR. Participants with profile 2 did not demonstrate differences in knee pain, symptoms, activities of daily living, sports function, or quality of life at 12 months after ACLR compared to those with profile 1 (P = .56-.81; η2 = 0.002-0.012). No statistically significant associations were noted between biomarker profiles and clinically relevant PTOA-related symptoms (odds ratio, 1.30; 95% CI, 0.23-6.33). CONCLUSION: Serum biomarker changes in MCP-1 and sCOMP within the first 6 months after ACLR were not associated with clinically relevant PTOA-related symptoms.

A new tool for early diagnosis of rheumatoid arthritis using combined biomarkers; synovial MAGE-1 mRNA and serum anti-CCP and RF.

INTRODUCTION: rheumatoid arthritis (RA) is a common autoimmune disease with unknown etiology and pathogenesis. Biomarkers have the potential to aid in the clinical diagnosis of the disease, or to provide means of detecting early signs of the disease. Evaluating Melanoma associated antigen genes (MAGE-1) mRNA expression rate in synovial fluid cells and serum levels of anti-cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) for RA early diagnosis. METHODS: a total of 213 subjects were enrolled in the study, 135 RA patients and 78 normal subjects with traumatic knee joints (control group). Serum RF and anti-CCP were estimated quantitatively using ELISA. MAGE-1 mRNA expression rate was analyzed by RT-PCR. RESULTS: a significant increase in serum levels of RF IgM and anti-CCP in RA patients compared to the controls. A positively significant correlation was found between serum anti-CCP and RF IgM. The expression rate of MAGE-1 mRNA was 100% in RA patients versus the controls (0%). The specificity and the sensitivity of the three biomarkers was 100%. CONCLUSION: the high expression rate of MAGE-1 in synovial fluid cells of RA patients is encouraging its utilization as a diagnostic biomarker for RA. The combined use of MAGE-1 transcript in synovial fluid cells, serum RF and anti-CCP is recommended for improving early diagnostic ability of RA.

Short-Term Outcomes of Percutaneous Trephination with a Platelet Rich Plasma Intrameniscal Injection for the Repair of Degenerative Meniscal Lesions. A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study.

Meniscal tears are the most common orthopaedic injuries, with chronic lesions comprising up to 56% of cases. In these situations, no benefit with surgical treatment is observed. Thus, the purpose of this study was to investigate the effectiveness and safety of percutaneous intrameniscal platelet rich plasma (PRP) application to complement repair of a chronic meniscal lesion. This single centre, prospective, randomized, double-blind, placebo-controlled study included 72 patients. All subjects underwent meniscal trephination with or without concomitant PRP injection. Meniscal non-union observed in magnetic resonance arthrography or arthroscopy were considered as failures. Patient related outcome measures (PROMs) were assessed. The failure rate was significantly higher in the control group than in the PRP augmented group (70% vs. 48%, P = 0.04). Kaplan-Meyer analysis for arthroscopy-free survival showed significant reduction in the number of performed arthroscopies in the PRP augmented group. A notably higher percentage of patients treated with PRP achieved minimal clinically significant difference in visual analogue scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) symptom scores. Our trial indicates that percutaneous meniscal trephination augmented with PRP results in a significant improvement in the rate of chronic meniscal tear healing and this procedure decreases the necessity for arthroscopy in the future (8% vs. 28%, P = 0.032).

Serum cartilage oligomeric matrix protein (COMP) expression in individuals who sustained a youth sport-related intra-articular knee injury 3-10 years previously and uninjured matched controls.

OBJECTIVE: This study investigates the relationship between a youth sport-related intra-articular knee injury and cartilage oligomeric matrix protein (COMP), a biomarker of cartilage turnover. DESIGN: Participants included a sub-sample (n = 170) of the Alberta Youth Prevention of Early Osteoarthritis (PrE-OA) study group. Specifically, 85 individuals with a 3-10 year history of sport-related intra-articular knee injury and 85 age, sex and sport-matched controls. COMP levels were investigated in serum. Between group differences in COMP levels, COMP fragmentation patterns and, the relationship between serum COMP and clinical outcomes (i.e., Magnetic Resonance Imaging (MRI) Osteoarthritis Knee Score; MOAKS, Knee Osteoarthritis Outcome Score; KOOS, Fat mass index; FMI) were examined. RESULTS: Participant median age was 22.3 years (range 16-26) and 63% were female. Although there was no difference in COMP levels between previously injured and uninjured females, previously injured males demonstrated an ∼15% greater (171.5 ng/ml, 95% CI 11.0-428.0, P = 0.04) serum COMP level than uninjured males. However after controlling for FMI, this difference was absent. Within the injured participants, COMP levels were associated with MOAKSSYNOVITIS and FMI. Furthermore, COMP fragmentation patterns were distinct between injured and uninjured individuals. CONCLUSIONS: In this study group, serum COMP levels were greater in injured males, but not females, compared to matched controls. However, after controlling for FMI, no differences in COMP were observed. A unique COMP fragmentation pattern was observed in injured vs uninjured participants. These results further the hypothesis that COMP levels and/or degradation of the protein may be a marker of cartilage injury which could predispose to later OA.

Serum Mast Cell Tryptase as a Marker of Posttraumatic Joint Contracture in a Rabbit Model.

OBJECTIVES: Mast cells have been identified as key mediators of posttraumatic joint contracture, and stabilizing medications (ketotifen) have been shown to decrease contracture severity. Serum mast cell tryptase (SMCT) levels are used clinically to monitor mast cell-mediated conditions. The goals of this study were to determine if SMCT levels are elevated in the setting of joint contracture, if they can be decreased in association with ketotifen therapy, and if they correlate with contracture severity. METHODS: This study used a previously developed rabbit model in which 39 animals were divided into 4 groups: operatively created joint contracture (ORC, n = 13), operatively created contracture treated with ketotifen at 2 doses (KF0.5, n = 9; KF1.0, n = 9), and healthy rabbits (NC, n = 8). Range of motion measures were performed at 8 weeks after the surgery. Serum samples were collected on postoperative days 1, 3, 5, 7, 21, 35, and 49. SMCT levels were measured using a rabbit-specific enzyme-linked immunosorbent assay. RESULTS: Levels of SMCT were highest in the operatively created joint contracture group and were significantly greater compared with both ketotifen groups (P < 0.001). Levels were highest at postoperative day 1 with a trend to decrease over time. A positive correlation between SMCT levels and contracture severity was observed in all operative groups (P < 0.05). CONCLUSIONS: Levels of SMCT are elevated in the setting of joint contracture, decreased in association with ketotifen therapy, and positively correlated with contracture severity. This is the first study to establish a relationship between SMCT and joint injury. Measurement of SMCT may be valuable in identifying those at risk of posttraumatic joint contracture.

Biochemical Response to a Moderate Running Bout in Participants With or Without a History of Acute Knee Injury.

CONTEXT: Individuals with an acute knee-injury history are 4 times more likely to develop knee osteoarthritis than those without a prior knee injury, and it is unknown why. Individuals with an injury history may exhibit aberrant changes in tissue turnover after physical activity (eg, running), which could lead to osteoarthritis, but this has yet to be determined among young, physically active individuals. OBJECTIVE: To determine collagen degradation and synthesis and inflammatory biomarker concentration levels before exercise and changes in response to an acute running bout in injured participants compared with healthy control participants. DESIGN: Cohort study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 22 physically active individuals between 18 and 25 years of age were recruited for the study: 11 injured participants (knee injury within 4 years of the study) who were medically cleared for physical activity and 11 matched healthy control participants. MAIN OUTCOME MEASURE(S): The independent variable was group (injured or control). Dependent variables were serum biomarker concentrations for cartilage oligomeric matrix protein, matrix metalloproteinase-13, proinflammatory marker interleukin-1ß, c-terminal cross-linking telopeptide of type II collagen, and type II collagen synthesis marker. Each participant provided prerun and postrun blood samples for biomarker-concentration analysis. RESULTS: No group differences existed in serum biomarker concentrations before exercise or in serum biomarker changes from pre-exercise to postexercise. CONCLUSIONS: After an acute bout of moderate-intensity running, young, active individuals in a high-risk postinjury population had similar biochemical responses as matched healthy controls. However, the external generalizability of these findings to other exercises and populations has yet to be determined.

Matrix metalloproteinase activity and prostaglandin E2 are elevated in the synovial fluid of meniscus tear patients.

PURPOSE: Meniscus tears are a common knee injury and are associated with the development of post-traumatic osteoarthritis (OA). The purpose of this study is to evaluate potential OA mediators in the synovial fluid and serum of meniscus tear subjects compared to those in the synovial fluid of radiographic non-OA control knees. MATERIALS AND METHODS: Sixteen subjects with an isolated unilateral meniscus injury and six subjects who served as reference controls (knee Kellgren-Lawrence grade 0-1) were recruited. Twenty-one biomarkers were measured in serum from meniscus tear subjects and in synovial fluid from both groups. Meniscus tear subjects were further stratified by tear type to assess differences in biomarker levels. RESULTS: Synovial fluid total matrix metalloproteinase (MMP) activity and prostaglandin E2 (PGE2) were increased 25-fold and 290-fold, respectively, in meniscus tear subjects as compared to reference controls (p < 0.05). Synovial fluid MMP activity and PGE2 concentrations were positively correlated in meniscus tear subjects (R = 0.83, p < 0.0001). In meniscus tear subjects, synovial fluid levels of MMP activity, MMP-2, MMP-3, sGAG, COMP, IL-6, and PGE2 were higher than serum levels (p < 0.05). Subjects with complex meniscus tears had higher synovial fluid MMP-10 (p < 0.05) and reduced serum TNFα and IL-8 (p < 0.05) compared to other tear types. CONCLUSIONS: Given the degradative and pro-inflammatory roles of MMP activity and PGE2, these molecules may alter the biochemical environment of the joint. Our findings suggest that modulation of PGE2 signaling, MMP activity, or both following a meniscus injury may be targets to promote meniscus repair and prevent OA development.

The complement system is activated in synovial fluid from subjects with knee injury and from patients with osteoarthritis.

BACKGROUND: The complement system is suggested to be involved in the pathogenesis of osteoarthritis (OA), and proinflammatory cytokines may play a role in OA development by inducing proteases. The association between complement factors, cytokines and OA has not been investigated. The aim of the present study was to explore the involvement of the complement system after knee trauma and in OA. METHODS: C4d, C3bBbP and soluble terminal complement complex (sTCC) resulting from complement activation were immunoassayed in synovial fluid from subjects with healthy knees (reference), OA, rheumatoid arthritis (RA; positive control), pyrophosphate arthritis (PPA; positive control) and knee injury; other biomarkers were previously assessed. Magnetic resonance imaging was used to assess joint injuries. RESULTS: Compared with levels in the reference group, the median concentrations of C4d, C3bBbP and sTCC in the OA, RA, PPA and knee injury groups were 2- to 34-fold increased (p < 0.001 to p = 0.044). For the knee injury group, the median concentrations of C4d, C3bBbP and sTCC were 5- to 12-fold increased (p < 0.001) at the day of injury; after 3-12 weeks, C3bBbP and sTCC concentrations were similar to reference levels; and C4d was still increased several years after injury. In the 0-12 weeks period after injury, the concentrations of C4d, C3bBbP and sTCC correlated positively with levels of interleukin (IL)-1ß, IL-6 and tumour necrosis factor α (r s range 0.232-0.547); none of the measured complement factors correlated with proteolytic fragments of aggrecan or cartilage oligomeric matrix protein. Knees with osteochondral fracture, with or without disrupted cortical bone, had higher concentrations of C4d (p = 0.014, p = 0.004) and sTCC (p = 0.004, p < 0.001) compared with knees without fractures. CONCLUSIONS: The complement system is activated in OA and after knee injury. Following knee injury, this activation is instant and associated with inflammation as well as with the presence of osteochondral fractures.

Circulating interleukin-6 is not altered while γ-tocopherol is increased in subjects scheduled for knee surgery with low vitamin D.

The purpose of this study was to identify if circulating interleukin (IL)-6 and γ-tocopherol (γT) fluctuate with vitamin D status in subjects with an underlying knee joint injury or disease. We hypothesized that low vitamin D associates with an increase in plasma γT while serum IL-6 remains unchanged in subjects with an underlying knee joint trauma or disease. Fifty-four subjects scheduled to undergo primary, unilateral anterior cruciate ligament reconstructive surgery (ACL; n=27) or total knee arthroplasty (TKA; n=27) were studied. Circulating γT, α-tocopherol (αT), lipids (cholesterol and triglycerides), IL-6, and 25-hydroxyvitamin D (25(OH)D) were measured in fasting blood samples obtained prior to surgery. Subjects were classified as vitamin D deficient, insufficient, or sufficient if they had a serum 25(OH)D concentration <50, 50-75, or >75nM, respectively. The majority (57%) of the subjects possessed a serum 25(OH)D less than 50nM. Circulating cholesterol, triglycerides, and IL-6 were not significantly (all p>0.05) different between vitamin D status groups. However, lipid corrected αT was significantly (p<0.05) decreased and both lipid- and non-lipid-corrected plasma γT concentrations were significantly (both p<0.05) increased with low serum 25(OH)D (i.e., <50nM). A significant (p<0.05) multi-variate analysis revealed that an increase in plasma γT per lipids was significantly (p<0.05) predicted by a decrease in serum 25(OH)D but not by a decrease in plasma αT per lipids. We conclude that low vitamin D associates with an increase in plasma γT but not IL-6 in subjects with an underlying joint injury or disease.

The incidence of deep venous thrombosis before arthroscopy among patients suffering from high-energy knee trauma.

PURPOSE: The purpose of the present study was to analyse the incidence of deep venous thrombosis (DVT) before knee arthroscopy in patients who had sustained high-energy knee injuries. METHOD: This study included 64 patients who underwent arthroscopic knee surgery as a result of injury from a traffic accident or a high fall. Venography was performed on the injured leg of each patient before arthroscopy. The patients were divided into two groups based on whether they had DVT. Correlation analysis was performed to determine the factors associated with DVT. RESULTS: A total of 32 (50 %) of the 64 patients had venographic evidence of DVT. Of these DVTs, seven were proximal (10.9 %). The D-dimer (DD) level was significantly higher in the DVT group, especially among the patients whose symptoms had persisted for more than 10 days. DVT is difficult to diagnose solely based on clinical symptoms, as some patients are symptomatic while others exhibit symptoms that could be attributed to trauma. CONCLUSIONS: The incidence of DVT before knee arthroscopy in patients with high-energy knee injuries was 50 %, and the prevalence of proximal DVT was 10.9 %. DD is a sensitive marker for DVT. No patient developed DVT with a DD level lower than 0.8 mg/L, but those with DD level higher than 1.5 mg/L had a much higher incidence of DVT developing in patients who had been injured for more than 10 days. A routine examination to exclude DVT in these patients should be performed before arthroscopy. LEVEL OF EVIDENCE: IV.

Acute Molecular Changes in Synovial Fluid Following Human Knee Injury: Association With Early Clinical Outcomes.

OBJECTIVE: To investigate whether molecules found to be up-regulated within hours of surgical joint destabilization in the mouse are also elevated in the analogous human setting of acute knee injury, how this molecular response varies between individuals, and whether it is related to patient-reported outcomes in the 3 months after injury. METHODS: Seven candidate molecules were analyzed in blood and synovial fluid (SF) from 150 participants with recent structural knee injury at baseline (<8 weeks from injury) and in blood at 14 days and 3 months following baseline. Knee Injury and Osteoarthritis Outcome Score 4 (KOOS4 ) was obtained at baseline and 3 months. Patient and control samples were compared using Meso Scale Discovery platform assays or enzyme-linked immunosorbent assay. RESULTS: Six of the 7 molecules were significantly elevated in human SF immediately after injury: interleukin-6 (IL-6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), activin A, and tumor necrosis factor-stimulated gene 6 (TSG-6). There was low-to-moderate correlation with blood measurements. Three of the 6 molecules were significantly associated with baseline KOOS4 (those with higher SF IL-6, TIMP-1, or TSG-6 had lower KOOS4 ). These 3 molecules, MMP-3, and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, after adjustment for other relevant factors. Of these, IL-6 alone significantly accounted for the molecular contribution to baseline KOOS4 and change in KOOS4 over 3 months. CONCLUSION: Our findings validate relevant human biomarkers of tissue injury identified in a mouse model. Analysis of SF rather than blood more accurately reflects this response. The response is associated with patient-reported outcomes over this early period, with SF IL-6 acting as a single representative marker. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent disease risk.

Type II collagen C2C epitope in human synovial fluid and serum after knee injury--associations with molecular and structural markers of injury.

PURPOSE: Investigate in a cross-sectional study time-dependent changes of synovial fluid type II collagen epitope C2C concentrations after knee injury and correlate to other joint injury biomarkers. METHODS: Synovial fluid samples were aspirated between 0 days and 7 years after injury (n = 235). Serum was collected from 71 of the knee injured patients. Synovial fluid from 8 knee-healthy subjects was used as reference. C2C was quantified by immunoassay and structural injury was determined from magnetic resonance images (MRI) of the injured knee acquired 1-38 days after injury (n = 98). Additional joint injury biomarker results were from earlier investigations of the same samples. RESULTS: Synovial fluid C2C concentrations were higher in injured knees than in knees of reference subjects from 1 day up to 7 years after injury. C2C concentrations in synovial fluid and serum were correlated (r = 0.403, P < 0.001). In synovial fluid from subjects early after injury (0-33 days), C2C concentrations were correlated with cross-linked C-telopeptide of type II collagen (r = 0.444, P = 0.003), ARGS-aggrecan (r = 0.337, P < 0.001), osteocalcin (r = 0.345, P < 0.001), osteopontin (r = 0.371, P < 0.001) and IL-8 (r = -0.385, P < 0.001), but not with structural joint injury as visualized on MRI. CONCLUSION: The increased levels of synovial fluid C2C after injury, together with the associations seen with several other injury-related biomarkers, suggest that an acute knee injury is associated with an immediate and sustained local degradation of type II collagen.

Adipokines as potential prognostic biomarkers in patients with acute knee injury.

This review considers adipokines as predictive biomarkers for early onset post-traumatic knee osteoarthritis (KOA). Serum concentrations of leptin and resistin can predict radiographic changes and are elevated in early KOA, with higher leptin concentrations independently associated with more severe knee changes. Plasma concentrations of resistin are chronically elevated after injury. Leptin, resistin, chemerin and vistfatin induce catabolic enzymes associated with cartilage degeneration. Available literature on adipokines in post-traumatic KOA pathogenesis suggests that they could contribute to risk prediction of early onset post-traumatic KOA. Further research is needed to further understand the association between adipokines, synovitis and long-term outcomes in this population.

Diurnal variation of serum chondroitin sulfate WF6 and hyaluronic acid in the healthy, traumatic knee and the osteoarthritic knee.

OBJECTIVE: An understanding of diurnal change is one of the important milestones for either biomarker validation or therapeutic level monitoring. The present study determines the most suitable period during the day for serum chondroitin sulfate WF6 (CS-WF6) and hyaluronic acid (HA) collection, and identifies the possible factors which affect the estimated putative half-life of serum CS-WF6 and hyaluronic acid (HA). MATERIAL AND METHOD: Forty-nine volunteers were enrolled in the present study, 22 healthy, 14 with anterior cruciate ligament (ACL) injury, and 13 volunteers with osteoarthritis (OA). Blood sample collection was carried out every four hours starting at 18.00 hours for 24 hours, with additional samples taken at 07:00 and 08:00 hours. Serum CS-WF6, HA levels were determined by an ELISA-based assay. RESULTS: The serum CS-WF6 level was significantly different between the normal and both pathological conditions. The serum HA level was significantly different in every condition. There was no diurnal pattern of serum CS-WF6 and HA during the 24 hour period. An estimated putative half-life of serum CS-WF6 and HA was 4.32 ± 2.63 and 4.10 ± 2.34, respectively. The maximum CS-WF6, creatinine clearance (CrCl) level and body mass index (BMI) were not related to the changes of the WF6 half-life. The higher maximum HA and CrCl level related to the longer half-life of serum HA level, p = 0.008 and p = 0.001, respectively. CONCLUSION: There was no diurnal pattern of serum CS-WF6 and HA due to the present study approach. Two hours after awakening in official time would be the suitable for serum CS-WF6. Two hours after awakening and after meals were suitable times for serum HA collection.

Evolution of C-reactive protein values in the first month after anterior cruciate ligament reconstruction: reference values.

PURPOSE: C-reactive protein (CRP) is often used as an infection marker in orthopaedic patients and in particular after anterior cruciate ligament (ACL) reconstruction surgery. The aim of this study is to obtain the reference values of CRP during the first month after an ACL reconstruction and to analyse the epidemiological and surgical parameters that affect these values. METHODS: One hundred and twenty ACL reconstructions were included. A CRP determination was performed preoperatively and 1, 7, 14, 21 and 28 days after surgery. CRP values under 5 mg/l were considered to be normal. RESULTS: One patient developed a septic arthritis in the second week postoperatively and was excluded. One hundred and seventeen patients [93 males and 24 females; mean age (standard deviation) 31.6 years (7.6)] underwent 119 ACL reconstructions with different techniques and grafts. Preoperative CRP (n = 119) was 1.80 mg/ml (2.6). Mean values at 1, 7, 14, 21 and 28 days were, respectively, 8.5 mg/ml (11.6), 10.5 mg/ml (17.0), 4.5 mg/ml (3.43), 4.4 mg/ml (7.59) and 3.4 mg/ml (3.03). Multivariate analysis showed that males had postoperative CRP levels 1.7 higher than females (p < 0.0001; 95 % CI 1.8-2.5); the patients operated by less experienced surgeons had levels 2.5 times higher than those operated by a highly experienced surgeons (p = 0.007; 95 % CI 1.2-3.4) and that if microfracture of a chondral lesion was associated, the levels increased 1.9 times (p = 0.021; 95 % CI 1.1-3.4). CONCLUSIONS: There are significant variations in CRP levels after ACL reconstruction in half of patients without infectious complications. Males, patients operated by less experienced surgeons and those with chondral lesions treated with microfracture had increased postoperative CRP levels. CRP values up to five times the normal limit are common in the month after an ACL reconstruction and are not necessarily associated with infection, especially in these groups.

Changes in serum biomarkers of cartilage turnover after anterior cruciate ligament injury.

BACKGROUND: Biomarkers of cartilage turnover and joint metabolism have a potential use in detecting early degenerative changes after a traumatic knee joint injury; however, no study has analyzed biomarkers before an anterior cruciate ligament (ACL) injury and again after injury or in comparison with a similar group of uninjured controls. HYPOTHESIS: Changes in serum biomarker levels and the ratio of cartilage degradation to synthesis, from baseline to follow-up, would be significantly different between ACL-injured patients and uninjured controls. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: This case-control study was conducted to examine changes in serum biomarkers of cartilage turnover following ACL injury in a young athletic population. Specifically, 2 markers for type II collagen and aggrecan synthesis (CPII and CS846, respectively) and 2 markers of types I and II degradation and type II degradation only (C1,2C and C2C, respectively) were studied. Preinjury baseline serum samples and postinjury follow-up samples were obtained for 45 ACL-injured cases and 45 uninjured controls matched for sex, age, height, and weight. RESULTS: Results revealed significant decreases in C1,2C (P = .042) and C2C (P = .006) over time in the ACL-injured group when compared with the controls. The change in serum concentrations of CS846 from baseline to follow-up was also significantly different between the ACL-injured patients and uninjured controls (P = .002), as was the change between groups in the ratio of C2C:CPII over time (P = .013). No preinjury differences in the ratio of C1,2C:CPII or C2C:CPII were observed between groups; however, postinjury differences were observed for both ratios. CONCLUSION: Changes in biomarker concentrations after an ACL injury suggest an alteration in cartilage turnover and joint metabolism in those sustaining ACL injuries compared with uninjured matched controls.

Serum non-coding RNAs as biomarkers for osteoarthritis progression after ACL injury.

OBJECTIVE: The aim of this study was to examine serum non-coding RNAs as potential biomarkers for cartilage damage associated with anterior cruciate ligament (ACL) injury. METHODS: Serum was obtained from 80 patients 1 year after surgery for ACL injury and 60 normal donors without overt skeletal injury. Total serum RNA was isolated, small non-coding RNAs profiled by TaqMan array MicroRNA (miRNA) analysis and individual small RNA assays performed by quantitative TaqMan RT-PCR (qPCR). Semi-quantitative magnetic resonance imaging (MRI) analysis was performed using Whole Organ Magnetic Resonance Knee Score (WORMS) scoring for analysis of cartilage damage. RESULTS: Initial TaqMan array miRNA profiling showed an increased serum concentration of a small nucleolar RNA (snoRNA), U48, in five patients with cartilage damage compared with that in five patients without cartilage damage and six normal donors. Independent qPCR analysis of snoRNAs in serum from all patients and normal donors showed a strong association between the serum level of another snoRNA, U38, and cartilage damage in ACL injury patients and together with snoRNA, U48, clear distinction between ACL injury patients and normal donors. CONCLUSION: SnoRNAs U38 and U48 are significantly elevated in the serum of patients developing cartilage damage at 1 year after ACL injury. Serum levels of U38 have the potential to facilitate early diagnosis of patients with cartilage damage after ACL injury. This study suggests serum non-coding RNAs may serve as novel noninvasive biomarkers for the detection and assessment of cartilage damage after ACL injury.

Longitudinal documentation of serum cartilage oligomeric matrix protein and patient-reported outcomes in collegiate soccer athletes over the course of an athletic season.

BACKGROUND: Serum cartilage oligomeric matrix protein (sCOMP) is a biomarker for cartilage degradation. Patient-reported outcomes (PRO) are used to document postinjury recovery and may be used to prospectively identify changes in the course of a season. It is unknown what effect intense, continuous physical activity has on sCOMP levels and PRO values in athletes over the duration of a soccer season. Hypothesis/ PURPOSE: The purpose of this study was to longitudinally document sCOMP levels and to determine whether changes in PROs occur in collegiate soccer athletes during a season. The hypotheses tested were that sCOMP levels and PRO scores would remain stable over the duration of the spring soccer season. STUDY DESIGN: Case series; level of evidence, 4. METHODS: Twenty-nine National Collegiate Athletic Association Division-I soccer athletes (18 men, 11 women; age, 19.6 ± 1.2 years; height, 177.8 ± 7.4 cm; mass, 73.8 ± 10.2 kg) participated in 3 (pre-[T(1)], mid-[T(2)], and postseason [T(3)]) data collection sessions. Subjects were included if they were participants in the spring soccer season and were free of severe knee injury at the time of data collection. At each session, subjects completed PROs (Lysholm, International Knee Documentation Committee scores) before serum collection. RESULTS: For sCOMP (ng/mL), there was a significant effect for time, with significant increases at T(2) (1723.5 ± 257.9, P < .001) and T(3) (1624.7 ± 231.6, P = .002) when compared with T(1)(1482.9 ± 217.9). For each of the PROs, there was a significant effect for time from T(1)-T(3), and at T(2)-T(3) for the IKDC. CONCLUSION: These data indicate sCOMP levels increased as athletes reported an increased level of function over time. However, the differences in sCOMP levels did not reach the calculated minimal detectable change (MDC) value and the differences in PRO scores did not reach previously calculated MDC values. It is unclear whether these increases in sCOMP levels were caused by an increase in cartilage matrix breakdown or turnover. Even though these elevations may not be clinically meaningful, this biomarker may have the potential to be used for future research studies investigating the effects of exercise on overall joint health in longitudinal studies. In addition, these results indicate fluctuations in sCOMP occur during a competitive season and must be taken into consideration for future biomarker studies.

Chondroitin sulfate epitope (WF6) and hyaluronic acid as serum markers of cartilage degeneration in patients following anterior cruciate ligament injury.

Serum chondroitin sulfate epitope (WF6) and hyaluronic acid (HA) levels were determined to be of clinical relevance to an anterior cruciate ligament (ACL) injury. This cross-sectional study recruited participants from two distinct groups. Group A was comprised of 74 healthy controls, and group B consisted of 33 ACL injury patients. Serum samples were taken and assayed by a competitive immunoassay with monoclonal antibody WF6. Serum HA was also determined by an ELISA-based assay using biotinylated HA-binding proteins. Both groups A and B shared similar values of age, body mass index, white blood cell count and percentage of polymorphonuclear cells. ESR levels were also shown to be within normal limits. The serum WF6 epitope levels of group B were significantly higher than those of group A, whereas serum HA levels were not different between the two groups. The serum WF6 epitope level is more sensitive to changes in articular cartilage due to a non-inflammatory instability condition than the serum HA level, and should prove to be one of the most promising assays for early post-traumatic arthritis detection.