Markers Of Joint Disease Research Articles

Quantitative Knee Arthrography in a Large Animal Model of Osteoarthritis Using Photon-Counting Detector CT.

The aim of this study was to grade cartilage damage in a swine model of osteoarthritis using a whole-body photon-counting detector (PCD) CT. A multienergy phantom containing gadolinium (Gd) (2, 4, 8, and 16 mg/mL) and hydroxyapatite (200 and 400 mg/cc) was scanned using a PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs, D50 reconstruction kernel) to serve as calibration for material decomposition and to assess quantification accuracy. Osteoarthritis was induced in Yucatan miniswine (n = 8) using 1.2 mg monoiodoacetate (MIA) injected into a randomized knee, whereas the contralateral control knee received saline. Twenty-one days later, a contrast bolus (gadoterate meglumine, 4 mL/knee) was intra-articularly administered into both knees. The knees were simultaneously scanned on the PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs). Multienergy images were reconstructed with a sharp "V71" kernel and a quantitative "D50" kernel. Image denoising was applied to the V71 images before grading cartilage damage, and an iterative material decomposition technique was applied to D50 images to generate the Gd maps. Two radiologists blinded to the knee injection status graded the cartilage integrity based on a modified International Cartilage Repair Society scoring system. Histology was performed on excised cartilage using methylene blue/basic fuchsin. Statistical analysis of grade distribution was performed using an exact test of omnibus symmetry with P < 0.05 considered significant. Material decomposed images from the multienergy phantom scan showed delineation and quantification of Gd and hydroxyapatite with a root-mean-squared error of 0.3 mg/mL and 18.4 mg/cc, respectively. In the animal cohort, the radiologists reported chondromalacia in the MIA knees with International Cartilage Repair Society scores ranging from grade 1 (cartilage heterogeneity, n = 4 knees) to grade 3 (up to 100% cartilage loss, n = 4 knees). Grade 1 was characterized by cartilage heterogeneity and increased joint space in the patellofemoral compartment, whereas grade 3 was characterized by cartilage erosion and bone-on-bone articulation in the patellofemoral compartment. All control knees were scored as grade 0 (normal cartilage). Significant difference (P = 0.004) was observed in the grade distribution between the MIA and control knees. Gross examination of the excised knees showed cartilage lesions in the grade 3 MIA knees. The Gd maps from material decomposition showed lower contrast levels in the joint space of the MIA knee compared with the contralateral control knee due to joint effusion. Histology revealed chondrocyte loss in the MIA knee cartilage confirming the chondrotoxic effects of MIA on cartilage matrix. We demonstrated a high-resolution and quantitative PCD-CT arthrography technique for grading cartilage damage in a large animal model of osteoarthritis. Photon-counting detector CT offers simultaneous high-resolution and multienergy imaging capabilities that allowed morphological assessment of cartilage loss and quantification of contrast levels in the joint as a marker of joint disease. Cartilage damage in the MIA knees was graded using PCD-CT images, and the image-based findings were further confirmed using histology and gross examination of the excised knees.

Influence of repeated arthrocentesis and exercise on synovial fluid concentrations of nitric oxide, prostaglandin E2 and glycosaminoglycans in healthy equine joints

The importance of osteoarthritis (OA) in the horse and the difficulty in its early diagnosis have led to a search for potential biomarkers of joint disease. If the levels of such markers are to be interpreted accurately, clinicians and researchers need to know whether they are influenced by environmental factors and/or interventions such as exercise and repeated arthrocentesis. To investigate the influence of repeated arthrocentesis and exercise on nitric oxide (NO), prostaglandin E2 (PGE2) and glycosaminoglycan (GAG) concentrations in synovial fluid (SF) from normal equine joints. SF was collected from the left metacarpophalangeal (MCP), radiocarpal and tarsocrural joints of 16 horses. Half of the horses were exercised and arthrocentesis was repeated 14, 14.5, 17 and 24 days after the start of the exercise programme, in both exercised and control horses. Nitric oxide was determined in SF from the MCP joint only and PGE2 and GAG concentrations were determined in SF from all joints. Repeated arthrocentesis caused an increase in NO concentration in the MCP joint on Day 145, in PGE2 concentrations in the radiocarpal and tarsocrural joints on Day 145 and the release of GAGs into SF of the MCP and radiocarpal joints on Day 17. Exercise resulted in an increase in PGE2 levels in all joints but did not influence the other parameters measured. Repeated arthrocentesis is a potential confounding factor for the use of synovial NO, PGE2 and GAG concentrations as markers of joint disease. Based on this study, such a confounding effect can be avoided if one week or more separates arthrocentesis procedures. Moderate exercise causes a transient rise in PGE2 in SF.

Diagnostic Importance of Deoxypyridinoline and Osteocalcine in Equine Osteoarthritis

Arican M., O. Koylu, A.Uyaroglu, M. Erol, K.N. Calim: Diagnostic Importance of Deoxypyridinoline and Osteocalcine in Equine Osteoarthritis. Acta Vet. Brno, 2004. 73: 491-496. In this study, deoxypyridinoline (Dpd) and osteocalcine (OC), which has been considered as a diagnostic and prognostic marker for joint disease in man and dog, was measured in urine from horses with osteoarthritis (OA). Serum and urinary assays of bone markers provide a noninvasive alternative to bone biopsy in the study of bone metabolism in horses. No significant differences in serum osteocalcine were found in either group. However, significant diferences were found in deoxypyridinoline/creatinine ratio between normal and OA urine. They may be useful in the monitoring of therapy and prognosis in horses with osteoarthritis. The measurement of collagen crosslink, deoxypyridinoline is comparatively more specific to monitor bone resorption. This article reviews the use of different bone markers in veterinary medicine and the possibilities for diagnosing and preventing bone diseases of horses. Horses, osteoarthritis, osteocalcine, deoxypyridinoline, degenerative joint disease. Degenerative joint disease (DJD) may be considered as a group of disorders characterized by a common endstage: progressive deterioration of the articular cartilage accompanied by changes in the bone and soft tissues of the joint. There have been various interpretations of

Neoepitopes as biomarkers of cartilage catabolism.

Progressive degradation of articular cartilage is a central feature of arthritis and a major determinant of long term joint dysfunction. There are no treatments able to halt the progression of cartilage destruction presently available, and monitoring the benefit of potential therapies is hampered by our inability to measure the "health" of articular cartilage. Serial radiographic assessment of joint space narrowing, the current gold standard, requires measurements over a prolonged time (1-5 years) and is prone to technical difficulties. Other strategies for evaluating cartilage degradation are needed to enable both short and long term monitoring of disease progression and response to therapy. One avenue that holds promise is the use of biomarkers that accurately reflect the degradative state of the articular cartilage. Antibodies that recognise terminal amino acid sequences generated by proteolysis at specific sites in the core protein of both aggrecan and type II collagen (neoepitope antibodies) have become available in recent years. These antibodies have been invaluable for identifying the proteinases responsible for cartilage breakdown both in vitro and in vivo. The presence of neoepitope sequences generated by specific metalloenzyme cleavage of aggrecan and type II collagen correlates well with the progression of cartilage degeneration, both in vitro and in mouse models of arthritis. Preliminary results with quantitative assays of type II collagen neoepitopes suggest that they may be useful markers of joint disease in humans. Long term studies correlating neoepitope concentration with clinical and radiographic disease are now required to validate the utility of neoepitopes as surrogate markers of cartilage degeneration and joint disease.

Synovial fluid cytokines and eicosanoids as markers of joint disease in horses.

To evaluate the value of various synovial fluid cytokines and eicosanoids to diagnose joint disease or categories of joint disease. Prospective acquisition of clinicopathologic data. Client-owned or donated horses: 50 joints with no evidence of disease; 28 joints with acute disease; 32 joints with chronic disease; 9 joints with cartilage damage and no other signs of joint disease. Concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), prostaglandin E(2) (PGE(2)), thromboxane B(2) (TXB(2)), prostaglandin F1-alpha (PGF(1)-alpha), and leukotriene B(4) (LTB(4)), were measured in equine synovial fluid by immunoassay and categorized according to duration and degree of joint disease. Any test value for a given category that was different from normal was further analyzed for sensitivity (S), specificity (Sp), and operating point (most valid test cutoff value). Likelihood ratios and predictive values were calculated at the operating point. Mediator concentrations were correlated to synovial fluid white blood cell count. Tests were reported as poor, fair, good, or excellent based on predictive values of <.25,.25-.5,.5-.75, or >.75, respectively. TNF synovial fluid concentration as a predictor of joint disease was good, and the value of TNF (maximum S and Sp) indicating joint disease was >36 pg/mL. IL-1beta as a predictor of joint disease was good, and the value of IL-1beta indicating joint disease was >4.5 pg/mL. IL-6 concentration was an excellent predictor of joint disease. Any IL-6 in synovial fluid indicated joint disease and correlated highly with synovial fluid white blood cell count (P <.0001). PGE(2) was a good-excellent predictor of disease (positive predictive value [PPV] = 0.75), and the concentration indicating joint disease was >22.5 pg/mL. The diagnostic PGF(1)-alpha concentration indicating severe chronic joint disease was identified to be >16.5 pg/mL with very high sensitivity (S = 1) and specificity (Sp =.89). PGF(1)-alpha concentrations > 9.5 pg/mL had a good PPV (.69) and NPV (.6) for any joint disease. TBX(2) concentrations below 31.5 pg/mL (S =.57; Sp =.61) were a very good predictor of joint disease (PPV =.72). LTB(4) concentration appeared to be greater in severe acute joint disease than normal joints; this was not significant (P =.15) and correlated highly with synovial fluid white blood cell count (P =.0001). The ability of a single value from a joint in an adult horse predicting the presence of joint disease was often good (.5-.75), and was excellent (> or =.75) for IL-6 and PGE(2). TNF-alpha and IL-1beta were no more effective than white blood cell count in screening for joint disease. IL-6 was the most sensitive and specific for joint disease and could be an excellent screening test for the presence of joint disease when lameness is difficult to identify or is intermittent. PGE(2) would be a functional screening test for the presence of any joint disease and offers a differentiating feature because values were not influenced by white blood cell count. PGF(1)-alpha values > 16.5 pg/mL identified chronic severe joint disease and may be clinically useful when there are minimal radiographic changes but substantial articular cartilage degradation.

Chondrex: new marker of joint disease

Chondrex, a major secretory protein of human chondrocytes and synovial fibroblasts, is increased in serum of patients with joint and cartilage disease. We have developed a sandwich-type ELISA for quantifying chondrex in serum. The interassay CVs were 2.8-3.7% and the average within-run and total CVs were 3.6% and 5.4%, respectively. The limit of detectability by linear dilution was 20 micrograms/L, recovery upon dilution was 102% +/- 5%, and analytical recovery (of added analyte) was 98% +/- 11%. The reference interval (central 90% interval) for chondrex in healthy adults was 25-95 micrograms/L. Chondrex values for patients with active rheumatoid arthritis or osteoarthritis were significantly greater than in healthy adults, inactive rheumatoid arthritis patients, and diabetes patients (P < 0.05). In patients treated with disease-modifying antirheumatic drug therapy, decreasing chondrex values reflected the clinical improvement observed in responders, whereas the values were maintained or increased in nonresponders. In conclusion, chondrex may be a useful marker in the clinical investigation of arthritis.

Effects of cyclosporin on serum hyaluronan levels in collagen arthritis.

Serum hyaluronan (HA) levels were measured in a rat model of collagen arthritis using a sandwich enzyme-linked immunosorbent assay. Values became elevated as the arthritis developed, correlating with its severity. Daily subcutaneous treatment with cyclosporin at the dose of 25 mg/kg per day for fourteen days completely prevented anti-type II collagen antibody production and the serum HA increase as well as development of collagen arthritis. HA in the blood may thus provide a good quantitative marker for joint disease in rat collagen arthritis with potential as a tool for evaluation of drug efficacy in this experimental model.

Hyaluronan in canine arthropathies

Soluble hyaluronan (HA), which has been considered as a marker for joint disease in man, was measured in serum and synovial fluid (SF) from dogs with osteoarthritis (OA), rheumatoid arthritis (RA), and rupture of the cranial cruciate ligament (CCL) and from normal dogs (control). Dogs with OA and RA had significantly increased serum HA (P < 0.001) and decreased synovial fluid HA (P < 0.001), as did dogs with CCL rupture (serum, P < 0.05; synovial fluid, P < 0.005). In OA, HA was lower in the SF from the affected joint than in that from the clinically normal (inactive) contralateral joint; no such difference was seen in dogs with CCL rupture. Dogs with liver disease (portocaval shunts, viral infectious hepatitis, metastatic neoplasm and disease secondary to diabetes mellitus) had increased serum HA concentrations (P < 0.001). There was a significant overlap of HA values in the diseased and normal dogs. Therefore, it is unlikely that the measurement of this cartilage breakdown product would be of value for diagnosis or prognosis in canine arthropathies.

Proteoglycans of joint cartilage: Structure, function, turnover and role as markers of joint disease

Joint cartilage consists of cells embedded in a matrix of fibrous collagen within a concentrated water-proteoglycan gel. The integrity of this matrix is crucial for the biomechanical properties of the joint cartilage. The different components of the matrix are synthesized and degraded by the cartilage cells, a process regulated by the amount of mechanical stress applied to the chondrocytes as well as by peptide factors and hormones present in synovial fluid. The proteoglycans are large macromolecules consisting of a protein core to which are attached multiple chains of glycosaminoglycans and oligosaccharides. During normal and pathological turnover, degradation products are released to the synovial fluid and to the circulation. Newly developed assays allow the sensitive and specific detection of these fragments in joint fluid and serum. Results of experimental and clinical investigations suggest that these assays will be of value in efforts to diagnose, grade and predict the outcome of inflammatory and degenerative joint disease.