Abstract
Bone tissue is continuously remodeled by the coordinated action of osteoclasts and osteoblasts. Nuclear factor-activated T cells c1 (NFATc1) is a well-known transcription factor for osteoclastogenesis and transcriptionally activated by the c-Fos and nuclear factor-kappa B (NF-κB) signaling pathways in response to receptor activation of NF-κB ligand (RANKL). Since excessive RANKL signaling causes an increase of osteoclast formation and bone resorption, inhibition of RANKL or its signaling pathway is an attractive therapeutic approach to the treatment of pathologic bone loss. In this study, we show that an ethyl acetate fraction (LEA) from the shiitake mushroom, Lentinula edodes, inhibited RANKL-induced osteoclast differentiation by blocking the NFATc1 signaling pathway. We found that the water extract and its subsequent ethyl acetate fraction of L. edodes significantly suppressed osteoclast formation. Comparative transcriptome analysis revealed that LEA specifically downregulated a set of RANKL target genes, including Nfatc1. Next, we found that LEA suppresses Nfatc1 expression mainly through the inhibition of the transactivity of p65 and NFATc1. Moreover, treatment of LEA rescued an osteoporotic phenotype in a zebrafish model of glucocorticoid-induced osteoporosis. Collectively, our findings define an undocumented role of the shiitake mushroom extract in regulating bone development.
Highlights
Bones are constantly degraded and regenerated throughout life
The formation of tartrate resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts was significantly inhibited by the water extract, but not by the ethyl acetate extract or the ethanol extract (Figure 1B and Supplementary Figure S1)
The findings that the water extract had no effect on the proliferation of osteoclast precursors indicate that the water extract directly controls the differentiation ability of OCP cells (Figure 1C)
Summary
Bones are constantly degraded and regenerated throughout life This process is known as bone remodeling, which is critical for bone shape and integrity [1]. Bone remodeling is carefully regulated by osteoclasts and osteoblasts Disturbing these processes leads to skeletal disorders, such as osteoporosis and osteopetrosis [2,3]. Glucocorticoids exert adverse effects on bone metabolism, including a decrease in the number and function of osteoblasts and an increase in the life span and differentiation of osteoclasts. Macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL) are two essential ligands for osteoclast differentiation. C-Fos and NF-κB signaling pathways activate nuclear factor-activated T cells c1 (NFATc1), a master transcription factor for osteoclastogenesis, subsequently stimulating the expression of diverse osteoclast-specific genes, such as tartrate resistant acid phosphatase (TRAP), cathepsin K, and osteoclast-associated receptor [9]. Treatment with LEA rescued the osteoporotic phenotype in an osteoporotic zebrafish model induced by prednisolone
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