Kartogenin-enhanced dynamic hydrogel ameliorates intervertebral disc degeneration via restoration of local redox homeostasis

Xin Tian; Yijian Zhang; Lei Shen; Guoqing Pan; Huilin Yang; Zhenhuan Jiang; Xuesong Zhu; Fan He

Journal of Orthopaedic Translation (Sep 2023)

Kartogenin-enhanced dynamic hydrogel ameliorates intervertebral disc degeneration via restoration of local redox homeostasis

Xin Tian,
Yijian Zhang,
Lei Shen,
Guoqing Pan,
Huilin Yang,
Zhenhuan Jiang,
Xuesong Zhu,
Fan He

Affiliations

Xin Tian: Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China
Yijian Zhang: Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China
Lei Shen: Department of Orthopaedics, The Affiliated Yixing Hospital of Jiangsu University, Yixing City, 214200, China
Guoqing Pan: Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University, Zhenjiang, 212013, China
Huilin Yang: Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China
Zhenhuan Jiang: Department of Orthopaedics, The Affiliated Yixing Hospital of Jiangsu University, Yixing City, 214200, China; Corresponding author. Department of Orthopaedics, The Affiliated Yixing Hospital of Jiangsu University, No. 75 Tongzhenguan Road, Yixing City, 214200, Jiangsu, China.
Xuesong Zhu: Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China; Corresponding author. Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, 215006, Jiangsu, China.
Fan He: Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China; Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China; Corresponding author. Orthopaedic Institute, Medical College, Soochow University, No. 178 East Ganjiang Road, Suzhou, 215000, Jiangsu, China.

Journal volume & issue: Vol. 42
pp. 15 – 30

Abstract

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Introduction: Over-activation of oxidative stress due to impaired antioxidant functions in nucleus pulpous (NP) has been identified as a key factor contributing to intervertebral disc degeneration (IVDD). While Kartogenin (KGN) has previously demonstrated antioxidant properties on articular cartilage against osteoarthritis, its effects on NP degeneration have yet to be fully understood. Objectives: This study aimed to investigate the protective effects of KGN on nucleus pulpous cells (NPCs) against an inflammatory environment induced by interleukin (IL)-1β, as well as to explore the therapeutic potential of KGN-enhanced dynamic hydrogel in preventing IVDD. Methods: NPCs were isolated from rat caudal IVDs and subjected to treatment with KGN at varying concentrations (ranging from 0.01 to 1 μM) in the presence of IL-1β. The expression of extracellular matrix (ECM) anabolism markers was quantitatively assessed at both the mRNA and protein levels. Additionally, intracellular reactive oxygen species and antioxidant enzyme expression were evaluated, along with the role of nuclear factor erythroid 2-related factor 2 (NRF2). Based on these findings, a dynamic self-healing hydrogel loaded with KGN was developed through interconnecting networks. Subsequently, KGN-enhanced dynamic hydrogel was administered into rat caudal IVDs that had undergone puncture injury, followed by radiographic analysis and immunohistochemical staining to evaluate the therapeutic efficacy. Results: In vitro treatments utilizing KGN were observed to maintain ECM synthesis and inhibit catabolic activities in IL-1β-stimulated NPCs. The mechanism behind this protective effect of KGN on NPCs was found to involve the asctivation of NRF2 and downstream antioxidant enzymes, including glutathione peroxidase 1 and heme oxygenase 1. This was further supported by the loss of both antioxidant and anabolic effects upon pharmacological inhibition of NRF2. Furthermore, a self-healing hydrogel was developed and loaded with KGN to achieve localized and sustained release of the compound. The injection of KGN-enhanced hydrogel effectively ameliorated the degradation of NP ECM and mitigated inflammation in a rat model of puncture-induced IVDD. Conclusions: Our results indicate that KGN exhibits potential as a therapeutic agent for NP degeneration, and that KGN-enhanced dynamic hydrogel represents a novel approach for treating IVDD by restoring redox homeostasis in NP.The translational potential of this article: The dysregulation of oxidant and antioxidant balance has been shown to impede the repair and regeneration of NP, thereby hastening the progression of IVDD following injury. The present investigation has demonstrated that the sustained release of KGN promotes the synthesis of ECM in vitro and mitigates the progression of IVDD in vivo by restoring redox equilibrium, thereby presenting a novel therapeutic candidate based on the antioxidant properties of KGN for the treatment of IVDD.

Published in Journal of Orthopaedic Translation

ISSN: 2214-031X (Print); 2214-0328 (Online)
Publisher: Elsevier
Country of publisher: Hong Kong
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the musculoskeletal system
Website: http://www.journals.elsevier.com/journal-of-orthopaedic-translation/

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