Ginkgo biloba extract promotes osteogenic differentiation of human bone marrow mesenchymal stem cells in a pathway involving Wnt/β-catenin signaling.
Human bone marrow derived mesenchymal stem cells (BM-MSCs) are a novel cell source used in stem cell therapy to treat bone diseases owing to their high potential to differentiate into osteoblasts. Effective induction of osteogenic differentiation from human BM-MSCs is critical to fulfill their therapeutic potential. In this study, Ginkgo biloba extract (GBE), a traditional herbal medicine, was used to stimulate the proliferation and osteogenic differentiation of human BM-MSCs. The present study revealed that GBE improved the proliferation and osteogenesis of human BM-MSCs in a dose-dependent manner in the range 25-75 mg/l, as indicated by alkaline phosphatase (ALP) activity and calcium content. However, such effect was decreased or inhibited at 100mg/l or higher. The dose-dependent improvement in osteogenesis of human BM-MSCs by GBE was further confirmed by the dose-dependent upregulation of marker genes, osteopontin (OPN) and Collagen I. The increased osteoprotegerin (OPG) expression and minimal expression of receptor activator of nuclear factor-κB ligand (RANKL) suggested that GBE also inhibited osteoclastogenesis of human BM-MSCs. Further mechanistic study demonstrated that the transcriptional levels of bone morphogenetic protein 4 (BMP4) and runt-related transcription factor 2 (RUNX2) in the BMP signaling, β-catenin and Cyclin D1 in the Wnt/β-catenin signaling, increased significantly during GBE-promoted osteogenesis. Meanwhile, loss-of-function assay with the signaling inhibitor(s) confirmed that the BMP and Wnt/β-catenin signaling pathways were indispensable during the GBE-promoted osteogenesis, suggesting that GBE improved osteogenesis via upregulation of the BMP and Wnt/β-catenin signaling. The present study proposed GBE to be used to upregulate the osteogenic differentiation of human BM-MSCs for new bone formation in BM-MSC-based cell therapy, which could provide an attractive and promising treatment for bone disorders.
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shanxi, China.
Qiuhan
Q
Gu
Department of Orthopedic Surgery, Jinan Military General Hospital of PLA, Jinan 250031, Shandong, China.
Chen
C
Chen
Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an 710054, Shanxi, China.
Zhengping
Z
Zhang
Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shanxi, China.
Zhigang
Z
Wu
Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shanxi, China.
Xiangli
X
Fan
Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shanxi, China.
Zhenyu
Z
Zhang
Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shanxi, China.
Wuweilong
W
Di
Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shanxi, China. Electronic address: lshi12345@163.com.
Lei
L
Shi
D000469:Alkaline Phosphatase / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects*; D055415:Bone Morphogenetic Protein 4 / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D051177:Catenins / Q000187:drug effects*; D024042:Collagen Type I / Q000096:biosynthesis; D050659:Core Binding Factor Alpha 1 Subunit / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020441:Ginkgo biloba / Q000737:chemistry*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D053495:Osteopontin / Q000096:biosynthesis; D010936:Plant Extracts / Q000494:pharmacology*; D053245:RANK Ligand / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000187:drug effects*
D055415:Bone Morphogenetic Protein 4; D051177:Catenins; D024042:Collagen Type I; D050659:Core Binding Factor Alpha 1 Subunit; D010936:Plant Extracts; D053245:RANK Ligand; C493709:RUNX2 protein, human; C505688:TNFSF11 protein, human; D051153:Wnt Proteins; D053495:Osteopontin; D000469:Alkaline Phosphatase; D002118:Calcium
BMP signaling; Bone marrow derived mesenchymal stem cell (BM-MSC); Ginkgo biloba extract (GBE); Osteogenesis; Wnt signaling