JD-312 – A novel small molecule that facilitates cartilage repair and alleviates osteoarthritis progression

Jingduo Gao; Haixiang Pei; Fang Lv; Xin Niu; Yu You; Liang He; Shijia Hu; Karan M. Shah; Mingyao Liu; Yihua Chen; Bing Du; Hai Xiong; Jian Luo

Journal of Orthopaedic Translation (Jan 2024)

JD-312 – A novel small molecule that facilitates cartilage repair and alleviates osteoarthritis progression

Jingduo Gao,
Haixiang Pei,
Fang Lv,
Xin Niu,
Yu You,
Liang He,
Shijia Hu,
Karan M. Shah,
Mingyao Liu,
Yihua Chen,
Bing Du,
Hai Xiong,
Jian Luo

Affiliations

Jingduo Gao: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China
Haixiang Pei: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China; Institute for Advanced Study, Shenzhen University and Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, PR China
Fang Lv: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China
Xin Niu: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China
Yu You: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China
Liang He: Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, PR China
Shijia Hu: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China
Karan M. Shah: Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield, United Kingdom
Mingyao Liu: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China
Yihua Chen: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China
Bing Du: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China; Corresponding author. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China.
Hai Xiong: Institute for Advanced Study, Shenzhen University and Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, PR China; Corresponding author. Shenzhen University and Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, 3688 Nanshan District, Shenzhen, PR China.
Jian Luo: Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, PR China; Corresponding author. Yangzhi Rehabilitation Hospital (Sunshine Rehabilitation Center), Tongji University School of Medicine, 2209 Guangxing Road, Shanghai, 201619, PR China.

Journal volume & issue: Vol. 44
pp. 60 – 71

Abstract

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Background: The chondrogenic differentiation of mesenchymal stem cells (MSCs) to enhance cartilage repair and regeneration is a promising strategy to alleviate osteoarthritis (OA) progression. Method: The potency of JD-312 in inducing chondrogenic differentiation of MSCs was assessed and verified. The efficacy of JD-312-treated MSCs was evaluated using a Sprague–Dawley rat DMM model. Additionally, the capacity of JD-312 to successfully recruit bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of OA in vitro was confirmed via intra-articular injection. The repair status of the articular cartilage was analyzed in vivo through histological examination. Result: In this study, we identify JD-312 as a novel non-toxic small molecule that can promote chondrogenic differentiation in human umbilical cord-derived MSCs (hUCMSCs) and human bone marrow MSCS (hBMSCs) in vitro. We also show that transient differentiation of MSCs with JD-312 prior to in vivo administration remarkably improves the regeneration of cartilage and promotes Col2a1 and Acan expression in rat models of DMM, in comparison to kartogenin (KGN) pre-treatment or MSCs alone. Furthermore, direct intra-articular injection of JD-312 in murine model of OA showed reduced loss of articular cartilage and improved pain parameters. Lastly, we identified that the effects of JD-312 are at least in part mediated via upregulation of genes associated with the focal adhesion, PI3K-Akt signaling and the ECM-receptor interaction pathways, and specifically cartilage oligomeric matrix protein (COMP) may play a vital role. Conclusion: Our study demonstrated that JD-312 showed encouraging repair effects for OA in vivo. The translational potential of this article: Together, our findings demonstrate that JD-312 is a promising new therapeutic molecule for cartilage regeneration with clinical potential.

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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