endothelin-1 and Osteoarthritis--Knee

Endothelin-1 (ET-1) is one of the probable inflammatory factors stimulating cartilage degradation in osteoarthritis (OA) pathogenesis.. To assess ET-1 level in OA and its correlation with radiographic findings, cartilage morphology and clinical parameters.. One hundred and thirty-nine subjects (89 OA, 50 controls) were included in this cross-sectional study. Both knee and hand joints of the participants were examined using plain radiography and ultrasound imaging by which distal femoral cartilage thickness/grading and second metacarpophalangeal cartilage thickness were assessed. Subjects were evaluated for pain and functional status using visual analogue scale, Western Ontario and McMaster Universities Arthritis Index and Duruöz Hand Index.. Serum ET-1 levels were higher in the OA group than the control group. Serum ET-1 levels were not correlated with cartilage thickness in patients with OA. Serum ET-1 levels were not correlated with either pain or other clinical parameters in the knee OA group and in the hand OA group.. This is the first study evaluating the relationship between serum ET-1 levels and cartilage morphology and clinical parameters, which did not show any conclusive result. Future studies, overcoming the limitations of this study, might provide a better understanding of the role of ET-1 in the pathogenesis of OA.

Topics: Biomarkers; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Female; Hand Joints; Humans; Knee Joint; Middle Aged; Osteoarthritis, Knee; Pain; Pain Measurement; Radiography; Severity of Illness Index; Ultrasonography

Endothelin-1, a potent vasoconstrictor regulator, contributes to articular cartilage destruction. Therefore, we aim to assess the correlation of endothelin-1 concentrations with the development and severity of knee osteoarthritis (OA). This study included a population of 209 patients with knee OA. Kellgren-Lawrence (KL) grading was utilized to score the severity of OA. The case group had higher serum endothelin-1 concentrations than controls. Patients with knee OA with a relatively higher grade showed significantly elevated serum and synovial fluid (SF) endothelin-1 concentrations compared with those with lower KL grades. A significant correlation was found between serum and SF endothelin-1 concentrations and KL grades. Serum and SF endothelin-1 concentrations are correlated with the development and progression of knee OA.

Topics: Case-Control Studies; Endothelin-1; Female; Humans; Male; Middle Aged; Osteoarthritis, Knee; Severity of Illness Index; Synovial Fluid

Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.. Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.. Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.. BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.

Topics: Animals; Anterior Cruciate Ligament; Arthralgia; Bradykinin; Bradykinin B1 Receptor Antagonists; Chronic Disease; Disease Models, Animal; Endothelin-1; Injections, Intra-Articular; Knee Joint; Male; Nociception; Osteoarthritis, Knee; Peptides, Cyclic; Rats; Rats, Inbred Lew; Weight-Bearing

The mechanism of endothelin-1 (ET-1)-induced nitric oxide (NO) production, MMP-1 production and MMP-13 production was investigated in human osteoarthritis chondrocytes. The cells were isolated from human articular cartilage obtained at surgery and were cultured in the absence or presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP). MMP-1, MMP-13 and NO levels were then measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and phosphorylated forms of p38 mitogen-activated protein kinase, p44/42, stress-activated protein kinase/Jun-N-terminal kinase and serine-threonine Akt kinase were determined by western blot. Results show that ET-1 greatly increased MMP-1 and MMP-13 production, iNOS expression and NO release. LY83583 decreased the production of both metalloproteases below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and was completely suppressed by the protein kinase A kinase inhibitor KT5720 and by LY83583, suggesting the involvement of these enzymes in relevant ET-1 signalling pathways. In human osteoarthritis chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. ET-1 and NO should thus become important target molecules for future therapies aimed at stopping cartilage destruction.

Topics: Aminoquinolines; Apoptosis; Carbazoles; Cartilage, Articular; Cells, Cultured; Chondrocytes; Collagenases; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Endothelin-1; Enzyme Induction; Female; Guanylate Cyclase; Humans; Imidazoles; Indoles; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type II; Osteoarthritis, Knee; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Processing, Post-Translational; Pyridines; Pyrroles; Signal Transduction