Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration
Ling Wu, … , Yunfeng Lin, Denis Evseenko
Ling Wu, … , Yunfeng Lin, Denis Evseenko
Published January 12, 2017
Citation Information: JCI Insight. 2017;2(1):e88553. https://doi.org/10.1172/jci.insight.88553.
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Research Article Bone biology

Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration

Abstract

Osteoarthritis is the most common form of arthritis, and pain relief with opioid-like drugs is a commonly used therapeutic for osteoarthritic patients. Recent studies published by our group showed that the kappa opioid receptor (KOR) is highly expressed during human development in joint-forming cells. However, the precise role of this receptor in the skeletal system remains elusive. The main aim of the current study was to investigate the role of KOR signaling in synovial and cartilaginous tissues in pathological conditions. Our data demonstrate that KOR null mice exhibit accelerated cartilage degeneration after injury when compared with WT mice. Activation of KOR signaling increased the expression of anabolic enzymes and inhibited cartilage catabolism and degeneration in response to proinflammatory cytokines such as TNF-α. In addition, selective KOR agonists increased joint lubrication via the activation of cAMP/CREB signaling in chondrocytes and synovial cells. Taken together, these results demonstrate direct effects of KOR agonists on cartilage and synovial cells and reveals a protective effect of KOR signaling against cartilage degeneration after injury. In addition to pain control, local administration of dynorphin or other KOR agonist represents an attractive therapeutic approach in patients with early stages of osteoarthritis.

Authors

Ling Wu, Shu Zhang, Ruzanna Shkhyan, Siyoung Lee, Francesca Gullo, Claire D. Eliasberg, Frank A. Petrigliano, Kai Ba, Jing Wang, Yunfeng Lin, Denis Evseenko

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Figure 6

Activation of kappa opioid receptor (KOR) signaling increases glycosaminoglycan content in cartilage explants from osteoarthritis patients.

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Activation of kappa opioid receptor (KOR) signaling increases glycosamin...
(A) Concentration of dynorphin in synovial fluid of normal individuals and osteoarthritis (OA) patients were measured with ELISA. Mean ± SD (n = 4). Each data point represents an average of 2 repeats for 1 donor. Four normal and 4 OA specimens were used for experimentation. (B) Cartilage explants were obtained from femoral condyles of OA patients who underwent total knee replacement. Explants were treated with U50,488H (U50) for 1 week. Alcian blue staining was performed to visualize the glycosaminoglycans (GAGs) in cartilage matrix. Scale bars: 100 μm. Representative images from 4 independent donors are shown. (C) GAG content in explants was measured using 1,9-dimethylmethylene blue (DMMB) assay. Mean ± SD (n = 4). Each data point represents an average of 3 repeats from each of 4 tissue donors. (D) Expression of enzymatic genes that compose the synthetic pathway of chondroitin sulfate. Mean ± SD (n = 4). XYLT1, xylosyltransferase I; β4GALT1, β-1,4-galactosyltransferase, polypeptide 1; β3GALT6, β-1,3-galactosyltransferase polypeptide 6; β3GAT3, β-1,3-glucuronyltransferase 3; GALNT1, UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 1. (E) Schematic depicts the model of how KOR/dynorphin (DYN) signaling protects cartilage tissue from posttraumatic degradation. P values were calculated with Student’s t test. Each data point represents the average of 3 repeats for 4 tissue donors.