Wedelolactone Enhances Osteoblastogenesis but Inhibits Osteoclastogenesis through Sema3A/NRP1/PlexinA1 Pathway.
Bone remodeling balance is maintained by tight coupling of osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Thus, agents with the capacity to regulate osteoblastogenesis and osteoclastogenesis have been investigated for therapy of bone-related diseases such as osteoporosis. In this study, we found that wedelolactone, a compound isolated fromEcliptae herba, and a 9-day incubation fraction of conditioned media obtained from wedelolactone-treated bone marrow mesenchymal stem cell (BMSC) significantly inhibited tartrate-resistant acid phosphatase (TRAP) activity in RANKL-stimulated osteoclastic RAW264.7 cells. Addition of the semaphorin 3A (Sema3A) antibody to the conditioned media partially blocked the medium's inhibitory effects on the RAW264.7 cells. In BMSC, mRNA expression of Sema3A increased in the presence of different wedelolactone concentrations. Blocking Sema3A activity with its antibody reversed wedelolactone-induced alkaline phosphatase activity in BMSC and concurrently enhanced wedelolactone-reduced TRAP activity in osteoclastic RAW264.7 cells. Moreover, in BMSC, wedelolactone enhanced binding of Sema3A with cell-surface receptors, including neuropilin (NRP)1 and plexinA1. Furthermore, nuclear accumulation of β-catenin, a transcription factor acting downstream of wedelolactone-induced Sema3A signaling, was blocked by the Sema3A antibody. In osteoclastic RAW264.7 cells, conditioned media and wedelolactone promoted the formation of plexin A1-NRP1, but conditioned media also caused the sequestration of the plexin A1-DNAX-activating protein 12 (DAP12) complex and suppressed the phosphorylation of phospholipase C (PLC)γ2. These data suggest that wedelolactone promoted osteoblastogenesis through production of Sema3A, thus inducing the formation of a Sema3A-plexinA1-Nrp1 complex and β-catenin activation. In osteoclastic RAW264.7 cells, wedelolactone inhibited osteoclastogenesis through sequestration of the plexinA1-DAP12 complex, induced the formation of plexinA1-Nrp1 complex, and suppressed PLCγ2 activation.
Institute (College) of Integrative Medicine, Dalian Medical University Dalian, China.
Yan-Qiu
YQ
Liu
Glucose and Lipid Metabolism Laboratory of Liaoning Province, College of Life Science and Technology, Dalian University Dalian, China.
Xiao-Fei
XF
Han
Glucose and Lipid Metabolism Laboratory of Liaoning Province, College of Life Science and Technology, Dalian University Dalian, China.
Jun-Xia
JX
Bo
College of Medical Laboratory, Dalian Medical University Dalian, China.
Hui-Peng
HP
Ma
NRP1; Sema3A; osteoblastogenesis; osteoclastogenesis; wedelolactone