Abstract
Bone homeostasis is maintained by formation and destruction of bone, which are two processes tightly coupled and controlled. Targeting both stimulation on bone formation and suppression on bone resorption becomes a promising strategy for treating osteoporosis. In this study, we examined the effect of wedelolactone, a natural product from Ecliptae herba, on osteoblastogenesis as well as osteoclastogenesis. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone stimulated osteoblast differentiation and bone mineralization. At the molecular level, wedelolactone directly inhibited GSK3β activity and enhanced the phosphorylation of GSK3β, thereafter stimulated the nuclear translocation of β-catenin and runx2. The expression of osteoblastogenesis-related marker gene including osteorix, osteocalcin and runx2 increased. At the same concentration range, wedelolactone inhibited RANKL-induced preosteoclastic RAW264.7 actin-ring formation and bone resorption pits. Further, wedelolactone blocked NF-kB/p65 phosphorylation and abrogated the NFATc1 nuclear translocation. As a result, osteoclastogenesis-related marker gene expression decreased, including c-src, c-fos, and cathepsin K. In ovariectomized mice, administration of wedelolactone prevented ovariectomy-induced bone loss by enhancing osteoblast activity and inhibiting osteoclast activity. Together, these data demonstrated that wedelolactone facilitated osteoblastogenesis through Wnt/GSK3β/β-catenin signaling pathway and suppressed RANKL-induced osteoclastogenesis through NF-κB/c-fos/NFATc1 pathway. These results suggested that wedelolacone could be a novel dual functional therapeutic agent for osteoporosis.
Highlights
Bone homeostasis is balanced by osteoblast-mediated bone formation and osteoclast-mediated bone resorption
The bone marrow mesenchymal stem cells (BMSC) obtained from BALB/c mice were cultured in an osteogenic medium (OS) containing 100 nM dexamethasone, 1 mM β-glycerophosphate, and 5 μM L-ascorbic acid 2-phosphate
When the cells were incubated with 1.25 μg/ml wedelolactone for 6, 9, and 12 d, the number of alkaline phosphatase (ALP)-positive BMSC increased with the most potent upon 9 d incubation. 1.25 μg/ml wedeloloactone increased the number of ALP-positive BMSC on the basis of observation of quantity and intensity of precipitated dye on the culture of these cells (Fig. 1B)
Summary
Bone homeostasis is balanced by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. For the anabolic agent parathyroid hormone (PTH), a concomitant increase in bone resorption can be observed[4,5] These drawbacks of the current therapies might be attributed to one target for these drugs that fail to uncouple bone degradation and formation: they stimulate or inhibit both processes at the same time. Activation of the canonical Wnt signaling pathway involves recruitment of a complex including LRP5/6 and GSK-3β, stabilization of β-catenin, regulation of transcription factors such as runx[2], and activation of Wnt target genes[16,17] This pathway is active in BMSC and many signaling molecules are developed as drug targets such as GSK-3βand LRP5/66. NFATc1 translocates to the nucleus and activates the expression of multiple osteoclastogenesis-related genes, such as cathepsin K, c-Src, and tartrate-resistant acid phosphatase (TRAP)
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