2. Academic Validation
  3. Glycyrol alleviates osteoporosis through dual modulation on osteoclastogenesis and osteogenesis by targeting Syk signaling pathway

Glycyrol alleviates osteoporosis through dual modulation on osteoclastogenesis and osteogenesis by targeting Syk signaling pathway

  • Phytomedicine. 2025 Mar:138:156429. doi: 10.1016/j.phymed.2025.156429.
Lihua Tan 1,  Yanbei Tu 2,  Zhimin Miao 1,  Yuxin Zhao 1,  Yongkai Liang 1,  Jinmiao Zhong 1,  Ruting Zhong 1,  Nan Xu 1,  Xin Chen 1,  Chengwei He 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China.
  • 2 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China; School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, 999078, China. Electronic address: chengweihe@um.edu.mo.
PMID: 39939034 DOI: 10.1016/j.phymed.2025.156429
Abstract

Background: Osteoporosis, characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation, has become a serious public health challenge worldwide. Glycyrol (GC) is a representative natural coumestan isolated from licorice that shows multiple pharmacological activities, but its anti-osteoporotic effect and underlying mechanisms remain unclear.

Results: GC significantly suppressed lipopolysaccharide-induced mouse bone loss and dexamethasone-induced zebrafish bone formation deficiency. Meanwhile, GC exhibited dual effects of inhibiting osteoclast formation and bone resorption, and stimulating osteoblast differentiation and mineralization. By combining kinomic screening assay, bioinformatics analysis and cellular target engagement validation, spleen tyrosine kinase (Syk) was identified as a key kinase target of GC. Subsequently, Syk was determined to play important roles in promoting osteoclast formation and impeding osteoblast differentiation. Interestingly, GC directly bound to the active cavity of Syk through hydrogen bonds and significantly inhibited its activity. Moreover, GC remarkably inhibited RANKL-induced activation of Syk/PLCγ2/CA2+/NFATc1 and MAPK pathways in macrophages undergoing differentiation into osteoclasts.

Conclusion: These results demonstrated that GC exerted a dual regulation on osteoclastogenesis and osteogenesis and consequently alleviated osteoporosis through targeting Syk and its downstream signaling pathways. In addition, the current study emphasizes the key roles of Syk in bone resorption and formation, suggesting the application potential of Syk inhibitors for the management of bone diseases. Meanwhile, this study provides evidence supporting the development of GC or its derivatives as effective anti-resorptive and bone anabolic agents for the prevention or treatment of osteoporosis and Other bone diseases.

Keywords

Glycyrol; Osteoclastogenesis; Osteogenesis; Osteoporosis; Spleen tyrosine kinase.

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