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Published on: March 18, 2022
Brief Report: JNK-2 Controls Aggrecan Degradation in Murine Articular Cartilage and the Development of Experimental
Heba M Ismail1, Jadwiga Miotla-Zarebska1, Linda Troeberg1
1Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuf-field Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford.
Objective:
The pathogenesis of osteoarthritis (OA) is poorly understood. Loss of the proteoglycan aggrecan from cartilage is an early event. Recently, we identified a role for the JNK pathway, particularly JNK-2, in human articular chondrocytes in vitro in regulating aggrecan degradation. The present study was undertaken to investigate whether JNK-2 has a similar function in vivo and to examine its role in gene expression.
Methods:
Aggrecan fragments were analyzed by Western blotting. OA was induced by destabilization of the medial meniscus (DMM) and assessed at 4, 8, and 12 weeks after surgery. Knee sections were stained with Safranin O. Medial compartments were scored by histologic grading for aggrecan loss and cartilage damage. RNA was extracted from JNK-2(-/-) and wild-type mouse knees 6 hours after DMM or after interleukin-1 stimulation of the proximal epiphysis, and expression of 33 DMM-regulated genes was analyzed with quantitative polymerase chain reaction-customized array cards.
Results:
In vitro, basal and interleukin-1- or tumor necrosis factor-stimulated release of aggrecanase-generated aggrecan fragments was greatly reduced in cartilage from JNK-2(-/-) mice. In the OA model, JNK-2(-/-) mice exhibited significant reduction of aggrecanase-generated fragments and cartilage damage. Of 33 genes investigated, 13 were significantly down-regulated in JNK-2(-/-) mice compared with wild-type mice, following DMM. These included Has1, Adamts4, Tnf, Il6, Il18, Il18rap, Il1a, Inhba, Cd68, Ngf, Ccr2, Wnt16, and Tnfaip6, but not Adamts5.
Conclusion:
Our results demonstrate that JNK-2 regulates aggrecan degradation in cultured murine cartilage and surgically induced OA in vivo following mechanical destabilization of the knee joint. This implicates the JNK signaling pathway in OA and suggests potential novel approaches to therapy.
Insights
JNK-2 signaling is crucial for aggrecan degradation in osteoarthritis (OA). Inhibiting JNK-2 in mice reduced cartilage damage and aggrecan loss in an OA model, suggesting new therapeutic targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Orthopedics
Background:
- Osteoarthritis (OA) pathogenesis is poorly understood, with aggrecan loss from cartilage being an early event.
- The c-Jun N-terminal kinase (JNK) pathway, specifically JNK-2, has been implicated in regulating aggrecan degradation in human articular chondrocytes.
- The in vivo role of JNK-2 in osteoarthritis and its impact on gene expression remain to be fully elucidated.
Purpose of the Study:
- To investigate the in vivo function of JNK-2 in regulating aggrecan degradation in a mouse model of osteoarthritis.
- To examine the role of JNK-2 in the gene expression changes associated with osteoarthritis.
- To determine if JNK-2 is a potential therapeutic target for osteoarthritis.
Main Methods:
- Osteoarthritis was induced in mice via destabilization of the medial meniscus (DMM) and assessed at 4, 8, and 12 weeks.
- Aggrecan fragments were analyzed using Western blotting, and knee sections were stained with Safranin O for histologic grading.
- Gene expression analysis of 33 DMM-regulated genes was performed using quantitative polymerase chain reaction in JNK-2 knockout and wild-type mice.
Main Results:
- JNK-2 knockout mice showed significantly reduced aggrecanase-generated fragments and cartilage damage in the DMM-induced OA model.
- In vitro studies demonstrated reduced aggrecan release from JNK-2 knockout mouse cartilage.
- Thirteen of 33 investigated genes were significantly downregulated in JNK-2 knockout mice post-DMM, including key inflammatory and matrix-degrading genes.
Conclusions:
- JNK-2 plays a significant role in regulating aggrecan degradation in both cultured cartilage and surgically induced osteoarthritis in vivo.
- The JNK signaling pathway is implicated in the pathogenesis of osteoarthritis.
- Targeting JNK-2 may offer novel therapeutic strategies for osteoarthritis treatment.
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