Urinary CTX-II Levels Research Articles

Can urinary CTX-II be a biomarker for knee osteoarthritis?

BackgroundEarly diagnosis of knee osteoarthritis (OA) remains a diagnostic challenge. Urinary C-terminal cross-linked telopeptide of type II collagen (urinary CTX-II) is one of the potential OA biomarkers. However, conclusive evidence regarding the use of this biomarker as a tool for early diagnosis is still lacking. The purposes of this study were to compare urinary CTX-II levels in patients with knee OA and in healthy controls, to evaluate the correlation between urinary CTX-II levels, radiographic severity of OA, and patient-reported outcomes and to evaluate the effect of age and gender on urinary CTX-II levels in the Asian populations.MethodsTwo groups were studied. The OA group included 78 patients with knee OA aged > 40 years who met the diagnostic criteria for knee OA described by the American College of Rheumatology (ACR). The control group consisted of 51 healthy participants age > 40 years without clinical or radiographic evidence of knee OA. Bilateral knee radiographs were taken and classified according to the Kellgren and Lawrence (KL) grading system. Urinary CTX-II was measured using a competitive ELISA test and Western Ontario and Mcmaster Universities Arthritis Index (WOMAC) was also recorded in all participants.ResultsUrinary CTX-II was significantly higher in the OA group than in the control group (p < 0.001). The severe knee OA group (KL grade 3 and 4) had higher urinary CTX-II levels than mild knee OA group (KL grade 2) but the difference did not reach statistical significance (p = 0.2). There was a moderate correlation between urinary CTX-II levels and KL grades (r = 0.405, p < 0.001) and a weak correlation between urinary CTX-II levels and WOMAC index scores (r = 0.367, p < 0.001). Multiple regression analysis showed that urinary CTX-II was independently associated with KL grades. Whereas age, gender, and WOMAC index had no statistically significant influence on the urinary CTX-II levels.ConclusionsPatients with knee OA had higher urinary CTX-II levels than healthy controls. Moreover, levels of urinary CTX-II were independently correlated with radiographic severity of knee OA. Age, gender, and patient-reported outcomes exerted no effect on the urinary CTX-II levels.Level of evidenceDiagnostic Level III.

The urinary levels of CTX-II, C2C, PYD, and Helix-II increased among adults with KBD: a cross-sectional study

BackgroundKashin-Beck disease (KBD) is an endemic osteoarthropathy, and its pathogenesis is still not entirely clear. Pathologically, many KBD changes are similar to those of osteoarthritis (OA). Therefore, this study aimed to identify changes in the levels of potential urinary biomarkers for OA, including C-telopeptide of type II collagen (uCTX-II), type II collagen cleavage neoepitope (uC2C), pyridinoline (uPYD), and uHelix-II, among adults with KBD.MethodsUrinary samples of 83 external control (EC) subjects, 91 KBD patients, and 86 internal control (IC) subjects were tested by ELISA after the subjects completed a questionnaire and X-ray examination.ResultsThe medians of the four markers in the KBD group were higher than those in the EC group and those in the IC group. The medians in the grade II KBD group were higher than those in the grade I group but were not statistically significant (P = 0.301, P = 0.408, P = 0.204, and P = 0.898 for uCTX-II, uC2C, uPYD, and uHelix-II, respectively). The area under the curve (AUC) of uCTX-II (0.775) was higher than that of the others (0.672, 0.639, and 0.628 for uC2C, uPYD, and uHelix-II, respectively).ConclusionThe levels of uCTX-II, uC2C, uPYD, and uHelix-II were elevated in adults with KBD and showed an increasing trend as the severity of KBD increased. The prediction accuracy of uCTX-II was more useful than that of the others for assisting in the diagnosis of KBD.

Knee Joint Distraction Compared with High Tibial Osteotomy and Total Knee Arthroplasty: Two-Year Clinical, Radiographic, and Biochemical Marker Outcomes of Two Randomized Controlled Trials.

ObjectiveBoth, knee joint distraction (KJD) and high tibial osteotomy (HTO) are joint-preserving surgeries that postpone total knee arthroplasty (TKA) in younger osteoarthritis (OA) patients. Here we evaluate the 2-year follow-up of KJD versus TKA and KJD versus HTO in 2 noninferiority studies.DesignKnee OA patients indicated for TKA were randomized to KJD (n = 20; KJDTKA) or TKA (n = 40). Medial compartmental knee OA patients considered for HTO were randomized to KJD (n = 23; KJDHTO) or HTO (n = 46). Patient-reported outcome measures were assessed over 2 years of follow-up. The radiographic joint space width (JSW) was measured yearly. In the KJD groups, serum-PIIANP and urinary-CTXII levels were measured as collagen type-II synthesis and breakdown markers. It was hypothesized that there was no clinically important difference in the primary outcome, the total WOMAC, when comparing KJD with HTO and with TKA.ResultsBoth trials were completed, with 114 patients (19 KJDTKA; 34 TKA; 20 KJDHTO; 41 HTO) available for 2-year analyses. At 2 years, the total WOMAC score (KJDTKA: +38.9 [95%CI 28.8-48.9] points; TKA: +42.1 [34.5-49.7]; KJDHTO: +26.8 [17.1-36.6]; HTO: +34.4 [28.0-40.7]; all: P < 0.05) and radiographic minimum JSW (KJDTKA: +0.9 [0.2-1.6] mm; KJDHTO: +0.9 [0.5-1.4]; HTO: +0.6 [0.3-0.9]; all: P < 0.05) were still increased for all groups. The net collagen type-II synthesis 2 years after KJD was increased (P < 0.05). Half of KJD patients experienced pin tract infections, successfully treated with oral antibiotics.ConclusionsSustained improvement of clinical benefit and (hyaline) cartilage thickness increase after KJD is demonstrated. KJD was clinically noninferior to HTO and TKA in the primary outcome.

C-Terminal Cross-Linked Telopeptides of Type II Collagen as Biomarker for Radiological Knee Osteoarthritis: A Meta-Analysis.

C-terminal cross-linked telopeptides of type II collagen (CTX-II) are one of the most frequently assessed markers for osteoarthritis (OA) diagnosis. The aim of this meta-analysis was to confirm the diagnostic value of urinary CTX-II in knee OA. PubMed, ScienceDirect, and EMBASE were searched for studies measured urinary CTX-II in patients with knee OA and in healthy controls. Urinary CTX-II levels were compared between knee OA patients and controls. Differences between groups were expressed as standardized mean differences (SMD) when individual outcomes were measured with different scales. Otherwise, outcomes were presented as mean differences (MD). Subgroup analyses were also conducted to compare efficiency of urinary CTX-II between Kellgren-Lawrence (KL) classification, genders, ethnicities, and study size. Thirteen studies involved a total of 2856 participants were included. Pooled SMD showed that urinary CTX-II levels were significantly elevated in knee OA group compared to controls (SMD 0.82; 95% CI 0.41-1.24; P < 0.0001). For KL 3 to 4 versus KL 2, higher urinary CTX-II levels were found in severe knee OA patients. Subgroup analyses revealed that urinary CTX-II performed better in females as compared with males and in European subjects as compared with Asian population. Also, study size did not influence the statistic results. This is the largest scale meta-analysis assessing the diagnostic performance of urinary CTX-II levels as biomarker for knee OA. According to our findings, urinary CTX-II levels have a potential to distinguish knee OA patients from healthy controls which can serve as biomarker for knee OA.

Association between US and MRI scores and correlations with urinary C-terminal telopeptide Type II collagen levels for early detection of hemophilic arthropathy of the knee

Assessment of knee hemophilic arthropathy (HA) requires objective measures. There is no consensus on a preferable ultrasonography (US) scoring system, whereas a reliable scoring system for magnetic resonance imaging (MRI) was developed by the International Prophylaxis Study Group of the World Federation of Hemophilia (IPSG-WFH). In this crosssectional study, a new US scoring system for early detection of knee HA was developed based on 25 peer-reviewed articles published between 1999 and 2015; furthermore, its associations with the MRI scoring system and urinary C-terminal telopeptide type II collagen (CTX-II) levels were investigated. In total, 27 children with severe hemophilia A were recruited. Early HA was confirmed using radiography as Arnold-Hilgartner stages 0–II. Knee MRI and US were scored using the MRI IPSG-WFH and new US scoring systems; urinary CTX-II levels were measured using enzyme-linked immunosorbent assay. Correlations were identified using Spearman test. The US scoring system included joint effusion, synovial hypertrophy and hypervascularization on power Doppler US, hemosiderin deposition, and cartilage damage. The US and MRI scores showed a moderate correlation; the US score and urinary CTX-II levels showed no correlation. The new US score can be used as an alternative to MRI for assessing early-stage kne HA.

Intra-articular Recombinant Human Proteoglycan 4 Mitigates Cartilage Damage After Destabilization of the Medial Meniscus in the Yucatan Minipig

Background: Lubricin, or proteoglycan 4 (PRG4), is a glycoprotein responsible for joint boundary lubrication. PRG4 has been shown previously to be down-regulated after traumatic joint injury such as a meniscal tear. Preliminary evidence suggests that intra-articular injection of PRG4 after injury will reduce cartilage damage in rat models of surgically induced posttraumatic osteoarthritis. Objective: To determine the efficacy of intra-articular injection of full-length recombinant human lubricin (rhPRG4) for reducing cartilage damage after medial meniscal destabilization (DMM) in a preclinical large animal model. Study Design: Controlled laboratory study. Methods: Unilateral DMM was performed in 29 Yucatan minipigs. One week after DMM, animals received 3 weekly intra-articular injections (3 mL per injection): (1) rhPRG4 (1.3 mg/mL; n = 10); (2) rhPRG4+hyaluronan (1.3 mg/mL rhPRG4 and 3 mg/mL hyaluronan [~950 kDA]; n = 10); and (3) phosphate-buffered saline (PBS; n = 9). Hindlimbs were harvested 26 weeks after surgery. Cartilage integrity was evaluated by use of macroscopic (India ink) and microscopic (safranin O–fast green and hematoxylin and eosin) scoring systems. Secondary outcomes evaluated via enzyme-linked immunosorbent assay (ELISA) included PRG4 levels in synovial fluid, carboxy-terminal telepeptide of type II collagen (CTX-II) concentrations in urine and serum, and interleukin 1β (IL-1β) levels in synovial fluid and serum. Results: The rhPRG4 group had significantly less macroscopic cartilage damage in the medial tibial plateau compared with the PBS group (P = .002). No difference was found between the rhPRG4+hyaluronan and PBS groups (P = .23). However, no differences in microscopic damage scores were observed between the 3 groups (P = .70). PRG4 production was elevated in the rhPRG4 group synovial fluid compared with the PBS group (P = .033). The rhPRG4 group presented significantly lower urinary CTX-II levels, but not serum levels, when compared with the PBS (P = .013) and rhPRG4+hyaluronan (P = .011) groups. In serum and synovial fluid, both rhPRG4 (P = .006; P = .017) and rhPRG4+hyaluronan groups (P = .009; P = .03) presented decreased IL-1β levels. Conclusion: All groups exhibited significant cartilage degeneration after DMM surgery. However, animals treated with rhPRG4 had the least amount of cartilage damage and less inflammation, providing evidence that intra-articular injections of rhPRG4 may slow the progression of posttraumatic osteoarthritis. Clinical Relevance: Patients with meniscal trauma are at high risk for posttraumatic osteoarthritis. This study demonstrates that an intra-articular injection regimen of rhPRG4 may attenuate cartilage damage after meniscal injury.

Biomarkers of prognosis and efficacy of treatment in OA

OA is a disease affecting the metabolism of all joint tissues leading to structural changes visible by imaging techniques. Unfortunately, features visible by imaging are in most cases irreversible and progressively moving towards worsening. One challenge for the next decade will be disease detection at the early stage when the first molecular/metabolic changes appear in joint tissues. Another challenge is to develop tools to assess the efficacy of OA treatment on the natural history of the disease. Therefore, there is an acute need for reliable biological markers that can facilitate earlier diagnosis of OA, predict the progression of the disease and evaluate the efficacy of therapeutic modalities. A recent literature review resulted in the identification of 16 biochemical markers investigating cartilage matrix turnover. Nine concerned collagen type II degradation (Coll2-1, Coll2-1NO2, CTX-II, Helix-II, C2C, TIINE, CIIM) and synthesis (PIIANP, PIICP). Keratan sulphate, chondroitin sulphate 846 (CS846) and ARGS-aggrecan fragment investigate proteoglycans degradation. Serum cartilage oligomeric matrix protein (COMP), deamidated-COMP (D-COMP), fibuline-3 fragments (Fib3-1 and Fib3-2) were the other biochemical markers that are considered as markers of cartilage matrix metabolism. Risedronate and strontium ranelate, two drugs currently used to treat osteoporosis decreased urinary CTX-II levels suggesting that they can modulate cartilage metabolism, even if they did not alter radiological progression. However, recently, it was demonstrated that CTX-II was more strongly associated with bone markers (i.e. uNTXI, uCTXI, serum PINP, and osteocalcin) than with other cartilage markers (PIIANP, sCS846, sCOMP), while the “other” cartilage markers were not so strongly associated with the bone markers. These data indicate that CTX-II might reflect bone rather than cartilage metabolism. In an exploratory study investigating the effects of three intra-articular injections of hyaluronic acid (Hylan GF-20) on the evolution of 10 biochemical markers, we have demonstrated that uCTXII, sColl2-1 and sColl2-1NO2 levels were significantly affected by treatment suggesting that these markers are sensitive to metabolic change occurring in one single joint. More recently, we have observed that three months treatment with bio-optimized curcumin significantly decreased sColl2-1 level in 24 patients with knee OA, suggesting that sColl2-1 could be a companion marker to assess curcumin efficacy at an individual level and in the next phases of its clinical development. Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. At this time, none of the existing biomarker can be considered as a surrogate marker of clinical and imaging feature for the diagnosis or prognosis of the disease. In this context, the recent development of large cohort designed to qualify biomarker will accelerate biochemical marker implementation in clinical research.

AB0082 The efficacy of anti-tnf treatment on urinary type-ii collagen c-telopeptyde levels in patients with rheumatoid arthritis

BackgroundThe aim of the present study was to evaluate the efficacy of anti-TNF treatment on urinary type-II collagen C-telopeptyde (CTX-II) levels which is a cartilage destruction marker in patients with...

Exploratory biomarker analysis reveals a genetic epistatic interaction in interleukin 1 receptor antagonist (IL1RN) gene associated to cartilage volume growth measured by MRI in response to sprifermin therapy in patients with knee radiographic osteoarthritis

Exploratory biomarker analysis reveals a genetic epistatic interaction in interleukin 1 receptor antagonist (IL1RN) gene associated to cartilage volume growth measured by MRI in response to sprifermin therapy in patients with knee radiographic osteoarthritis

TNF-α is elevated in synovial fluid of patients with an anterior cruciate ligament rupture 5 years after the injury. Pro-inflammatory cytokines in synovial fluid and serum – a prospective longitudinal study

s / Osteoarthritis and Cartilage 21 (2013) S63–S312 S72 Purpose: Hand osteoarthritis (OA) is one of the most common localization of OA, affecting predominantly women. Patients with knee, hip or spine OA exhibit increased cartilage type II collagen degradation as detected by the urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II), but data on hand OA are lacking. The aim of this study was to investigate the relationship between urinary CTX-II and hand OA in women. Subjects and Methods: We investigated 590 women from the OFELY population-based study (mean age: 61.8 years 10.2) including 475 postmenopausal women. Clinical hand OAwas defined according to the ACR criteria (Altman et al, 1990) slightly modified (without functional complains). At the same time of hand OA evaluation, knee and spine OA were assessed by radiographs and self-reported hip OA was recorded. Levels of urinary CTX-II measured by ELISA (Urine CartiLaps , IDS) in the 186 women with hand OA (mean age: 67.2 years 8.4) were compared to those of the 404 other women without hand OA (mean age: 59.4 years 10.1). All analyses were adjusted for age and concomitant knee, hip or spine OA. Results: Urinary CTX-II levels were significantly increased in women with hand OA (+ 45% vs controls, p1⁄4 0.001) after adjustment for age and for knee, spine and hip OA). When urinary CTX-II concentrations were considered in quartiles, subjects with levels in the highest quartile had an increased risk of presenting with hand OA, with an odds-ratio of 2.06 (95% CI: 1.3-3.2; p 1⁄4 0.002) after adjustment for OA at the other anatomical sites. Conclusion: Hand OA is characterized by increased type II collagen degradation. Urinary CTX-II could be a useful biomarker for the clinical investigation of hand OA. 118 TNF-a IS ELEVATED IN SYNOVIAL FLUID OF PATIENTS WITH AN ANTERIOR CRUCIATE LIGAMENT RUPTURE 5 YEARS AFTER THE INJURY. PRO-INFLAMMATORY CYTOKINES IN SYNOVIAL FLUID AND SERUM – A PROSPECTIVE LONGITUDINAL STUDY M. Hansson y, S. Larsson y, R. Frobell y, L.S. Lohmander y,z, A. Struglics y. y Lund Univ., Clinical Sci. Lund, Lund, Sweden; zRes. Unit for Musculoskeletal Function and Physiotherapy, and Dept.s of Orthopaedics and Traumatology, Univ. of Southern Denmark, Odense, Denmark Purpose: Trauma induced cytokine response in knee injuries may play a role in the development of osteoarthritis (OA) since knee injuries are Table 1 Cytokine concentrations (pg/ml) in SF and serum expressed as medians (25th–75th percen at different time. Half LLOQ values: IL-10, 1.0; IL-6, 0.3; IFN-g, 0.6.

Impact of treatments for osteoporosis on cartilage biomarkers in humans

The rationale to target bone for treating osteoarthritis (OA) relies on the known cross-talk between subchondral bone and cartilage and the demonstration that subchondral bone resorption occurs at an early stage in the development of OA. Therefore, the possible OA disease-modifying effects of bone antiresorptive agents are of interest. This paper aims to review the published data on the effect of estrogens, selective estrogen receptor modulators, calcitonin, strontium ranelate, and bisphosphonates on cartilage biomarkers levels used as surrogate endpoints in clinical trials. Except for findings for tibolone, most observations indicated that these antiresorptive therapies decreased the urinary levels of CTX-II, a biomarker of type II collagen degradation. These data, which should be cautiously interpreted, suggest that these drugs might favorably affect cartilage homeostasis.

Prevention of cartilage degeneration and gait asymmetry by lubricin tribosupplementation in the rat following anterior cruciate ligament transection

To investigate whether cartilage degeneration is prevented or minimized in a rat model of anterior cruciate ligament (ACL) injury following a single dose-escalated intraarticular injection of lubricin derived from human synoviocytes in culture. Unilateral ACL transection (ACLT) of the right hind limb was performed in Lewis rats (n = 56). Control animals underwent a capsulotomy alone, leaving the ACL intact (n = 11). Intraarticular injections (50 μl/injection) of phosphate buffered saline (PBS; n = 14 rats) and human synoviocyte lubricin (1,600 μg/ml; n = 14 rats) were performed on day 7 postsurgery. Animals were killed on day 70 postsurgery. Histologic specimens were immunoprobed for lubricin and sulfated glycosaminoglycans. Urinary C-telopeptide of type II collagen (CTX-II) levels were measured on days 35 and 70 postsurgery. Hind limb maximum applied force was determined using a variable resistor walkway to monitor quadruped gait asymmetries. Increased immunostaining for lubricin in the superficial zone and on the surface of cartilage was observed in lubricin-treated and control animals but not in PBS-treated or untreated animals with ACLT. On days 35 and 70 after surgery, urinary CTX-II levels in human synoviocyte lubricin-treated animals were lower than in untreated and PBS-treated animals (P < 0.005 and P < 0.001, respectively). Animals with ACLT treated with human synoviocyte lubricin and control animals distributed their weight equally between hind limbs compared to PBS-treated or untreated animals (P < 0.01). Our findings indicate that a single intraarticular injection of concentrated lubricin following ACLT reduces type II collagen degradation and improves weight bearing in the affected rat joint. These findings support the practice of tribosupplementation with lubricin for retarding cartilage degeneration and possibly the development of posttraumatic osteoarthritis.

Association of serum levels of aggrecan ARGS, NITEGE fragments and radiologic knee osteoarthritis in Tunisian patients

ObjectivesProteolytic degradation of aggrecan is a hallmark of the pathology of osteoarthritis. The aim of this study was to develop enzyme-linked immunosorbent assay (ELISA) to quantify the serum levels of specific aggrecan fragments generated by aggrecanases-mediated cleavage. We investigated the relationships between these two aggrecan degradations fragments and urinary CTX-II levels. MethodsThe competitive ELISAs employ a polyclonal antibody raised against the aggrecan fragments containing two neoepitopes NITEGE373and 374ARGSVI. We measured serum levels of ARGSV and NITEGE in 125 women with knee osteoarthritis (mean±SD age of 53.6±7.6 years, mean±SD disease duration of 3.6±3.8 years), and 57 women age-matched controls. ResultsAggrecan neoepitopes assays showed an intra- and inter-assay imprecision (CV) lower than 20% for both tests and good linearity. Median serum ARGSVI (by 18%; P=0.002), and NITEGE (36.4%; P<0.001) levels were significantly decreased in patients with knee osteoarthritis compared with controls. Minimal joint space width was negatively correlated with ARGSVI (r=–0.368, P=0.04) and NITEGE (r=–0.274, P=0.038) in knee osteoarthritis patients. Median urinary CTX-II levels were significantly increased by 39.5% (P=0.001) in knee OA patients compared with controls. ConclusionMarkers of degradation aggrecan were analyzed for the first time in an African osteoarthritis population. These markers can be used to monitor aggrecanase activity in human joint disease. Their combination with CTX-II can improve clinical investigation of patients with osteoarthritis patients.

Polymerized-Type I Collagen Downregulates Inflammation and Improves Clinical Outcomes in Patients with Symptomatic Knee Osteoarthritis Following Arthroscopic Lavage: A Randomized, Double-Blind, and Placebo-Controlled Clinical Trial

Objectives. Polymerized-type I collagen (polymerized collagen) is a downmodulator of inflammation and cartilage regenerator biodrug. Aim. To evaluate the effect of intraarticular injections of polymerized collagen after arthroscopic lavage on inflammation and clinical improvement in patients with knee osteoarthritis (OA). Methods. Patients (n = 19) were treated with 6 intraarticular injections of 2 mL of polymerized collagen (n = 10) or 2 mL of placebo (n = 9) during 3 months. Followup was 3 months. The primary endpoints included Lequesne index, pain on a visual analogue scale (VAS), WOMAC, analgesic usage, the number of Tregs and proinflammatory/anti-inflammatory cytokine-expressing peripheral cells. Secondary outcomes were Likert score and drug evaluation. Clinical and immunological improvement was determined if the decrease in pain exceeds 20 mm on a VAS, 20% of clinical outcomes, and inflammatory parameters from baseline. Urinary levels of C-terminal crosslinking telopeptide of collagen type II (CTXII) and erythrocyte sedimentation rate (ESR) were determined. Results. Polymerized collagen was safe and well tolerated. Patients had a statistically significant improvement (P < 0.05) from baseline versus polymerized collagen and versus placebo at 6 months on Lequesne index, VAS, ESR, Tregs IL-1β, and IL-10 peripheral-expressing cells. Urinary levels of CTXII were decreased 44% in polymerized collagen versus placebo. No differences were found on incidence of adverse events between groups. Conclusion. Polymerized collagen is safe and effective on downregulation of inflammation in patients with knee OA.

Prevention of cartilage degeneration and restoration of chondroprotection by lubricin tribosupplementation in the rat following anterior cruciate ligament transection.

To investigate whether cartilage degeneration is prevented or minimized following intraarticular injections of lubricin derived from human synoviocytes in culture, recombinant human PRG4 (rhPRG4), or human synovial fluid (SF) in a rat model of anterior cruciate ligament (ACL) injury. Unilateral ACL transection (ACLT) was performed in Lewis rats (n = 45). Nine animals were left untreated. The remaining rats were given intraarticular injections (50 microl/injection) of either phosphate buffered saline (PBS) (n = 9), human synoviocyte lubricin (200 microg/ml; n = 9), rhPRG4 (200 microg/ml; n = 9), or human SF lubricin (200 microg/ml; n = 9) twice weekly beginning on day 7 after injury. Joints were harvested on day 32 after injury. Histologic analysis was performed using Safranin O-fast green staining, and articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Histologic specimens were immunoprobed for lubricin and sulfated glycosaminoglycans. A 24-hour urine collection was performed on days 17 and 29 postinjury, and urinary C-terminal telopeptide of type II collagen (CTX-II) levels were measured. Treatment with human synoviocyte lubricin resulted in significantly lower OARSI scores for cartilage degeneration compared with no treatment or PBS treatment (P < 0.05). Increased immunostaining for lubricin in the superficial zone chondrocytes and on the surface of cartilage was observed in lubricin-treated, but not untreated or PBS-treated, joints. On day 17, urinary CTX-II levels in human synoviocyte lubricin- and human SF lubricin-treated animals were significantly lower than those in untreated animals (P = 0.005 and P = 0.002, respectively) and in PBS-treated animals (P = 0.002 and P < 0.001, respectively). After treatment with any of the 3 types of lubricin evaluated in this study, a reduction in cartilage damage following ACLT was evident, combined with a reduction in type II collagen degradation. Our findings indicate that intraarticular lubricin injection following an ACL injury may be beneficial in retarding the degeneration of cartilage and the development of posttraumatic OA.

Skin and urine pentosidine weakly correlate with joint damage in a cohort of patients with early signs of osteoarthritis (CHECK)

Age-related changes in articular cartilage are likely to play a role in the aetiology of osteoarthritis (OA). One of the major age-related changes in cartilage is the accumulation of advanced-glycation-endproducts (AGEs). Since, cartilage tissue is not readily available from patients for studying AGE levels, alternative approaches such as analyzing skin and urine are needed to study the role of cartilage AGE levels in OA. Paired human skin and cartilage samples were obtained post mortem. Paired skin and urine samples were obtained from the CHECK cohort (early OA patients). Pentosidine levels were measured by high-performance liquid chromatography (HPLC). As marker of cumulative cartilage damage X-rays of both knees and hips were scored. Urinary CTXII (uCTXII) levels were measured, to assess current cartilage breakdown. Cartilage and skin pentosidine correlate well (R=0.473, P=0.05). Skin pentosidine was higher in mild (summed (Kellgren & Lawrence K&L) over four large joints ≥4) compared to no (summed K&L≤3) radiographic OA (P=0.007). Urinary pentosidine was not different between these two groups. Skin pentosidine levels were not related to cartilage breakdown (highest vs lowest tertile of uCTXII). Urinary pentosidine, however, was higher in the highest compared to the lowest uCTXII tertile (P=0.009). Multiple regression analysis showed age to be the only predictor of the summed K&L score and age, creatinine clearance and urinary pentosidine as predictors of uCTXII. The higher skin and urinary pentosidine levels in those with mild compared to no radiographic joint damage and low vs high cartilage breakdown respectively suggest that AGEs may contribute to disease susceptibility and/or progression. However, relations are weak and cannot be used as surrogate markers of severity of OA.

A longitudinal analysis of urinary biochemical markers and bone mineral density in STR/Ort mice as a model of spontaneous osteoarthritis

To investigate the longitudinal changes both in the urinary concentrations of biochemical markers and in bone mineral density (BMD) during disease progression in the STR/Ort mouse model of osteoarthritis (OA). Male STR/Ort mice were studied, with CBA mice used as nonarthritic controls. Radiographic evaluation and grading of the knee and measurements of urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II), pyridinoline (Pyr), and deoxypyridinoline were performed between 8 weeks and 40 weeks of age. The BMD of the femoral shaft was measured from 20 weeks to 40 weeks of age and adjusted for body weight. Histologic evaluation and grading were performed at 40 weeks of age. STR/Ort mice were divided into 2 subgroups (STR OA and STR non-OA) based on histologic grading. No significant differences between STR/Ort and CBA mice were observed for any biochemical marker or BMD at any time point. Urinary CTX-II levels and BMD in the STR OA subgroup were higher than those in the STR non-OA subgroup before radiographic changes of OA were apparent. Higher urinary Pyr levels in the STR OA subgroup were observed at the advanced stage of OA. Urinary CTX-II could be a useful marker in the early diagnosis and predicting the progression of OA, and urinary Pyr may be a potential marker to assess the severity of OA at an advanced stage. An increase in BMD prior to the establishment of radiographic OA may be related to the induction of OA.

Intra-articular hyaluronic acid increases cartilage breakdown biomarker in patients with knee osteoarthritis

Intra-articular hyaluronic acid has been used in treatment of patients with knee osteoarthritis. Though its effect on pain has been well studied, it is not clear how it affects the articular cartilage. This is a preliminary study to evaluate the kinetics of urinary collagen type-II C-telopeptide (CTX-II) as a biomarker of collagen breakdown in response to intra-articular hyaluronic acid injection in patients with symptomatic knee osteoarthritis. Intra-articular injections of hyaluronan were administered to ten patients with symptomatic knee osteoarthritis. Urine collection for urinary CTX-II was obtained at baseline, before each injection and once every other week for a total of 6 months. Urine CTX-II was measured using a CartiLaps(c) ELISA kit. There was a statistically significant increase (p = 0.0136) in CTX-II a week after the third intra-articular injection of hyaluronic acid (6,216 ng/mmol +/- 4,428) compared with baseline (2,233 ng/mmol +/- 1,220). This increase in CTX-II was sustained throughout the entire 6 months follow-up period (repeated measures ANOVA, p < 0.015). This is the first study of changes in an osteoarthritis biomarker after intra-articular hyaluronic acid injections in patients with symptomatic knee osteoarthritis. Contrary to our initial hypothesis that CTX-II levels should decrease after intra-articular hyaluronic acid injections, we found a significant increase in urinary CTX-II levels that was sustained throughout the study. These observations suggest that intra-articular hyaluronic acid injections may accelerate cartilage breakdown in patients with symptomatic knee osteoarthritis. The responsible mechanisms are unknown and warrant further study.

Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training

To investigate changes in levels of serum cartilage oligomeric matrix protein (COMP) and urine c-telopeptide of type-2 collagen (CTX-II) as markers for cartilage turnover in patients with osteoarthritis (OA) of the knee, in response to muscle strength training in combination with treatment with glucosamine, ibuprofen or placebo. A 12-week double blind, placebo controlled, randomized study. Thirty-six elderly patients with bilateral tibiofemoral knee OA determined by radiography were randomly assigned to treatment with glucosamine (n=12), ibuprofen (n=12) or placebo (n=12) during 12 weeks of strength training of both legs with focus on the quadriceps muscle. Strength tests (5 repetition maximum), blood and urine sampling were performed before and after the training period. Serum COMP and urinary CTX-II were measured by enzyme-linked immunosorbent assay (ELISA). All three groups increased their muscle strength following 12 weeks of strength training (P<0.001). Serum COMP levels were reduced in the glucosamine-treated group after the training period (P=0.012), whereas they did not change in the two other groups. Glucosamine reduced COMP statistically significant compared to both placebo and ibuprofen; the mean reduction with glucosamine was 13% vs placebo (P=0.0378) and 17% vs ibuprofen (P=0.0122). Urinary CTX-II levels did not change significantly in any of the three experimental groups. Serum COMP decreased significantly over the 12-week training period when treatment with glucosamine was added to the training regimen. This suggests an effect by glucosamine on the response of the OA cartilage to a period of joint loading in humans with knee OA.

The response to oestrogen deprivation of the cartilage collagen degradation marker, CTX-II, is unique compared with other markers of collagen turnover

IntroductionThe urinary level of the type II collagen degradation marker CTX-II is increased in postmenopausal women and in ovariectomised rats, suggesting that oestrogen deprivation induces cartilage breakdown. Here we investigate whether this response to oestrogen is also true for other type II collagen turnover markers known to be affected in osteoarthritis, and whether it relates to its presence in specific areas of cartilage tissue.MethodsThe type II collagen degradation markers CTX-II and Helix-II were measured in the body fluids of premenopausal and postmenopausal women and in those of ovariectomised rats receiving oestrogen or not. Levels of PIIANP, a marker of type II collagen synthesis, were also measured in rats. Rat knee cartilage was analysed for immunoreactivity of CTX-II and PIIANP and for type II collagen expression.ResultsAs expected, urinary levels of CTX-II are significantly increased in postmenopausal women and also in oestrogen-deprived rats, although only transiently. However, in neither case were these elevations paralleled by a significant increase of Helix-II levels and PIIANP levels did not change at any time. CTX-II immunoreactivity and collagen expression were detected in different cartilage areas. The upper zone is the area where CTX-II immunoreactivity and collagen expression best reflected the differences in urinary levels of CTX-II measured in response to oestrogen. However, correlations between urinary levels of CTX-II and tissue immunostainings in individual rats were not statistically significant.ConclusionsWe found only a small effect of oestrogen deprivation on cartilage. It was detected by CTX-II, but not by other type II collagen turnover markers typically affected in osteoarthritis.