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 4

Dynorphin A inhibited the catabolic effects of TNF-α in cartilage explants.

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Dynorphin A inhibited the catabolic effects of TNF-α in cartilage explan...
(A) Cartilage explants were treated with basal medium or basal medium supplemented with TNF-α (10 ng/ml) alone or basal medium with TNF-α (10 ng/ml) and dynorphin A (1 μM). Dynorphin A attenuated glycosaminoglycan (GAG) loss and the activation of catabolic enzymes caused by TNF-α. Scale bars: 500 μm for top row of safranin O–stained sections, 100 μm for all other images. (B) Real-time PCR was performed to examine the expression levels of catabolic genes in cartilage explants. Mean ± SD (n = 3). (C) Hydroxyproline assay was performed to measure total collagen in cartilage explants treated with TNF-α or TNF-α+dynorphin A. Mean ± SD (n = 3). (D) 1,9-Dimethylmethylene blue (DMMB) assay was used to determine the GAG content in cartilage explants. Mean ± SD (n = 3). (E and F) Dynorphin A inhibits TNF-α–induced apoptosis in articular chondrocytes. Mean ± SD (n = 3). P values in all panels were calculated with 1-way ANOVA followed by Tukey honest significant difference post-hoc test. Each data point represents an average of 3 counts from each tissue donor. Images shown in A and F are representative of 3 independent experiments (3 different tissue donors). FSC, forward scatter.