In vivo and in vitro aggrecanases degrade proteoglycan aggrecan in articular cartilage. However, the expression of aggrecanases in patients in different stages of osteoarthritis (OA) has not been investigated. This study detected the expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) and ADAMTS-5 and their proteolytic products, ARGxx, in the synovial fluid (SF) of patients in different stages of OA. This study aimed to evaluate the expression of aggrecanases and to explore the respective roles of these enzymes in human cartilage degradation. A total of 144 patients with knee OA were divided into early-, middle-, and late-stage OA groups according to the degree of cartilage degradation using Recht's MRI grading standard and the modified Outerbridge classification system. Expression levels of ADAMTS-4, ADAMTS-5, and ARGxx in the SF from these patients were measured using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Our findings showed that ADAMTS-4 and ARGxx expression levels in the early-stage group were significantly higher than in the other two groups. ADAMTS-5 in the early-stage group and ADAMTS-4, ADAMTS-5, and ARGxx in the late-stage group were significantly higher than those in the middle-stage OA group. Both ADAMTS-4 and ADAMTS-5 levels were correlated with ARGxx levels (P < 0.05). The correlation coefficients of ADAMTS-4 and ADAMTS-5 were 0.236 and 0.068, 0.729 and 0.479, and 0.675 and 0.257 in the early-, middle-, and late-stage groups, respectively, and 0.530 and 0.258 in the total SF samples. Western blot analysis revealed that the ADAMTS-4 and ADAMTS-5 in SF were 50 kDa proteins and that ARGxx in SF had at least two molecular masses, 55 kDa and 70 kDa. The expression levels of all three proteins were consistent with the ELISA results. These results suggested that aggrecanases were involved in all stages of human OA aggrecan degradation, especially in the early and late stages. ADAMTS-4 levels were higher in early- compared with middle- or late-stage OA and were also more correlated with ARGxx than ADAMTS-5; thus, ADAMTS-4 might be the principal aggrecanase of aggrecan degradation in human OA.

Level IV, retrospective case series.

Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc.