2. Academic Validation
  3. Genkwanin blocks the interaction between phosphorylated JNK and NFATc1 to promote osteogenic differentiation and collagen Ⅰ α1 production

Genkwanin blocks the interaction between phosphorylated JNK and NFATc1 to promote osteogenic differentiation and collagen Ⅰ α1 production

  • Eur J Pharmacol. 2025 Jul 15:999:177687. doi: 10.1016/j.ejphar.2025.177687.
Yu-Xuan Hao 1,  Yong-Yan Chen 1,  Xu Han 2,  Xu Wang 3,  Fu-Peng Wu 4,  Cai-Ling Wen 1,  Tong-Qing Chen 1,  Sheng Tan 1,  Dan-Dan Zheng 1,  Yang Hong 5,  Xiao-Yan Shen 6
Affiliations

Affiliations

  • 1 Department of Pharmacology & Quzhou Fudan Institute, School of Pharmacy, Fudan University, Shanghai, China.
  • 2 Department of Orthopedics, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China; Shanghai Clinical Research Center for Aging and Medicine, Shanghai, China; Center of Community-Based Health Research, Fudan University, Shanghai, China.
  • 3 Department of Orthopedics, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China; Shanghai Clinical Research Center for Aging and Medicine, Shanghai, China; Center of Community-Based Health Research, Fudan University, Shanghai, China; Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 4 Department of Pharmacology & Quzhou Fudan Institute, School of Pharmacy, Fudan University, Shanghai, China; Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China.
  • 5 Department of Orthopedics, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China; Shanghai Clinical Research Center for Aging and Medicine, Shanghai, China; Center of Community-Based Health Research, Fudan University, Shanghai, China. Electronic address: hongyangcm@163.com.
  • 6 Department of Pharmacology & Quzhou Fudan Institute, School of Pharmacy, Fudan University, Shanghai, China; Department of Orthopedics, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China; Shanghai Clinical Research Center for Aging and Medicine, Shanghai, China; Center of Community-Based Health Research, Fudan University, Shanghai, China; The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai, China. Electronic address: shxiaoy@fudan.edu.cn.
PMID: 40311832 DOI: 10.1016/j.ejphar.2025.177687
Abstract

Genkwanin (GWA), a flavonoid compound found abundantly in various traditional Chinese medicines, has demonstrated pharmacological effectiveness against a range of diseases. However, its role in bone formation and the underlying mechanisms remain to be elucidated. The aim of this study is to investigate the effects of GWA on osteogenic differentiation and to uncover the possible mechanisms. Primary bone marrow-derived mesenchymal stem cells (BMSCs) and MC3T3-E1 cells induced for osteogenic differentiation were used as in vitro cell models. An ovariectomy (OVX) mouse model to induce secondary osteoporosis was used to evaluate the in vivo pharmacologic efficacy of GWA. Our studies revealed that GWA facilitated osteogenic differentiation and bio-mineralization of BMSCs and MC3T3-E1 cells in vitro, and could effectively prevent OVX-induced systematic bone loss and Collagen Ⅰ α1 (COL1A1) reduction in vivo. Mechanism studies indicated that GWA could directly bind to phosphorylated c-Jun N-terminal kinase (pJNK) to prevent the phosphorylation of nuclear factor of activated T cells 1 (NFATc1) by JNK, thereby promote osteogenic differentiation and COL1A1 production via increasing the nuclear localization of NFATc1. This is distinct from the previously recognized function of the JNK/AP-1/NFATc1 signaling pathway in activating osteoclast differentiation. More importantly, GWA had no significant effects on estrogen-related signaling pathways, indicating a unique advantage in lowering the risk of gynecological Cancer. In conclusion, our data suggest that GWA may be a promising candidate for the therapy of diseases associated with bone loss. Targeting pJNK-NFATc1 interaction may represent a new strategy to stimulate osteogenesis.

Keywords

COL1A1; Genkwanin; JNK; NFATc1; OSX; Osteogenic differentiation.

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