This study investigated the role of apoptosis signal-regulated kinase-1 (ASK1) in intervertebral disc degeneration (IDD). The nucleus pulposus (NP) tissues of non-IDD and IDD patients were subjected to hematoxylin and eosin, Safranin O-fast green, and immunohistochemical staining. Quantitative real-time PCR was used to assess the ASK1 mRNA level within NP tissue samples and cells. The Cell Counting Kit-8 assay, senescence-associated β-galactosidase staining, and then flow cytometry were conducted, respectively, to assess the viability, senescence, and apoptosis of NP cells. The extracellular matrix-related factors were detected using Western blot analysis. Furthermore, the effect of ASK1 on the IDD rat model was evaluated through nuclear magnetic resonance imaging analysis, hematoxylin and eosin, Safranin O-fast green staining, and immunohistochemical staining. Finally, c-Jun N-terminal kinase (JNK) inhibitors were used to verify the effect of the JNK/p38 signaling on IDD. ASK1 mRNA and protein were up-regulated within NP tissue samples from the IDD group, IL-1β-stimulated NP cells, and IDD rats. ASK1 inhibition promoted cell viability and repressed the senescence and apoptosis of NP cells; promoted collagen II and aggrecan; inhibited matrix metalloproteinase 3, matrix metalloproteinase 9, a disintegrin and metalloproteinase with thrombospondin motifs 4, and a disintegrin and metalloproteinase with thrombospondin motifs 5 protein levels; and increased NP cells in rat intervertebral disc tissues. ASK1 overexpression exerted the opposite effects of ASK1 inhibition on NP cells. Additionally, JNK/p38 signaling suppression could reverse the ASK1 up-regulation-induced dysfunction. In conclusion, ASK1 facilitated the senescence and apoptosis of NP cells in promoting IDD progression, which may be mediated by the JNK/p38 pathway.

01 Aug 2024·Current Medicinal Chemistry

Combining Mendelian Randomization Analysis and 3D-QSAR to Investigate the Effectiveness of a New Series of Hydroxyquinolines in Osteoarthritis

Article

Author: Su, Kunpeng ; Lu, Hui ; Qu, Changpeng ; Ma, Xuexiao ; Lian, Zheng

Background:Osteoarthritis (OA) represents a persistent degenerative joint ailment. As OA advances, profound joint pain coupled with diminished joint function inflicts substantial physical distress and psychological strain on patients. Presently, pharmacological solutions for arthritis remain limited, primarily encompassing analgesics and joint replacement surgical procedures. Hence, non-operative strategies to mitigate osteoarthritis progression have captured significant attention in orthopedic research.Objective:This study aims to discern a definitive causal linkage between ADAMTS-4/5 and osteoarthritis through Mendelian randomization analysis.:Moreover, it seeks to anticipate the therapeutic efficacy of a suite of emergent hydroxyquinolines for osteoarthritis using the Quantitative Structure-Activity Relationship (QSAR) methodology.Methods:Within this study, genetic variants specific to knee osteoarthritis were procured as exposure variables from a genome-wide association study (GWAS). Genetic variant data for ADAMTS-4/5 served as the endpoint to evaluate the causal nexus employing univariate Mendelian randomization. This analysis underpins the hypothesis that ADAMTS-4/5 presents a promising therapeutic target for osteoarthritis management. The suppressive properties of novel hydroxyquinolines against ADAMTS-4/5 were subsequently examined through conformational analyses, underscoring the potential of these compounds as therapeutic candidates for osteoarthritis.Results:IVW outcomes from the Mendelian randomization revealed a significant association of KOA (OR: 1.1675, 95% CI: 1.0003-1.3627, P = 0.0495) with ADAMTS-5. However, KOA (OR: 1.0801, 95% CI: 0.9256-1.2604, P = 0.3278) displayed no evident connection with ADAMTS-4. Notably, the instrumental variables manifested neither heterogeneity nor horizontal pleiotropy. In this research endeavor, 16 pharmacological models were formulated via the CoMSIA method within 3D conformational relationship evaluations. A synergistic interplay of hydrophobic, spatial, and hydrogen-bonded receptor domains emerged as the most predictively potent. The cross-validation coefficient q2 for the optimum model stood at 0.716, with a principal component score of 5, a regression coefficient r2 of 0.971, a standard estimation error of 0.351, and an f-value of 156.951. Such metrics intimate the commendable predictive prowess of our devised CoMSIA models.Conclusion:The research unearthed a robust causal interrelation between ADAMTS-5 and osteoarthritis via Mendelian randomization. Furthermore, a credible drug model targeting ADAMTS-5 was constructed. Collectively, these findings illuminate a path forward in the pursuit of target-specific drugs for osteoarthritis management in subsequent investigations.

01 Mar 2024·Histology and histopathology

Catalpol protects mouse ATDC5 chondrocytes against interleukin-1β-induced catabolism.

Article

Author: Cai, Chengkui ; Sun, Pengcheng ; Sun, Chao ; Chen, Zhihui ; Tian, Liying

Catalpol is a natural product with promising anti-inflammatory effects, however, its effects on chondrocytes and osteoarthritis (OA) have not been well investigated. OA is a painful and debilitating joint disease that affects people worldwide. Traditional Chinese Medicine has been sought to treat OA, including the Rehmannia extract, Catalpol. Here, we examined the effects of Catalpol, a plant derivative used in traditional Chinese medicine, on ATDC5 chondrocytes originating from mouse teratocarcinoma cells stimulated with interleukin-1β (IL-1β) to mimic the OA cellular environment. Catalpol significantly reduced matrix metalloproteinase-1, -3, -13 (MMP-1, -3, -13), a disintegrin and metalloproteinase with thrombospondin motifs -4, -5 (ADAMTS-4, -5) against IL-1β, demonstrating a likely anti-cartilage degradation activity. We also found that Catalpol exerted a significant anti-oxidative stress effect by downregulating the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO), reactive oxygen species (ROS), and malondialdehyde (MDA). Catalpol treatment significantly reduced the levels of several key inflammatory factors, including Prostaglandin E₂ (PGE₂), cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). We further demonstrate that the effects of Catalpol were mediated by the nuclear factor -κB (NF-κB) pathway via downregulation of the phosphorylation of inhibitor of nuclear factor κB-α (IκBα). This was confirmed by measuring p38 and p65 protein levels as well as the luciferase activity of NF-κB. Altogether, we demonstrate the potential of Catalpol as a novel treatment agent against cartilage matrix degradation, oxidative stress, and inflammation in OA.

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