Abstract
The phytochemical substances, coumarin derivatives, have demonstrated antiresorptive bone effects by suppressing osteoclast differentiation in vitro and in vivo. Recently, we have identified 5′-hydroxy auraptene (5′-HA), a coumarin derivative isolated from Lotus lalambensis Schweinf, as a novel stimulator for osteoblast differentiation. In this study, we investigated the effect of 5′-HA on osteoclast differentiation of mouse bone marrow (BM) cells. The effect of 5′-HA on BM cell proliferation and osteoclast differentiation was determined by measuring cell viability and tartrate-resistant acid phosphatase (TRAP) enzyme activity, quantification of TRAP+ multinucleated cells (TRAP+MNCs), and quantitative real-time PCR (qPCR) of osteoclastic gene expression. Regulation of NF-κB, c-Fos/NFATc1, and MAPK signaling pathways by 5′-HA during osteoclastogenesis was measured by the NF-κB reporter assay and Western blot analysis. 5′-HA significantly suppresses the receptor activator of NF-κB ligand (RANKL) induced osteoclast differentiation of BM cells in a dose-dependent manner. Consistently, treatment of BM cells with 5′-HA significantly inhibited RANKL-induced activation of NF-κB and c-Fos/NFATc1 pathways in a dose-dependent manner. Furthermore, RANKL-induced phosphorylation of ERK1/2, p-38, and JNK was significantly inhibited by 5′-HA in BM cells. In conclusion, we identified 5′-HA as a novel coumarin derivative that suppresses RANKL-induced osteoclastogenesis via inhibiting c-Fos/NFATc1 and MAPK signaling pathways.
Highlights
Osteoporosis is an endocrine-metabolic bone disease that is characterized by disorders in the bone remodeling process toward increased bone resorption by osteoclasts over the expenses of bone formation by osteoblasts [1]
NFATc1 plays a vital role in osteoclast maturation and activation via upregulating the gene expression of osteoclastic-related genes including matrix metalloproteinase (Mmps), Trap, and Cathepsin K (Ctsk) [6,7,8,9]. us, targeting osteoclast formation and differentiation via inhibiting NF-κB and MAPK signaling are an effective strategy toward preventing bone loss related diseases [10, 11]
bone marrow (BM) cells treated with M-CSF and Receptor activator of nuclear factor kappa-Β (RANKL) displayed the formation of multinucleated osteoclasts in association with increasing tartrate-resistant acid phosphatase (TRAP) enzyme activity in osteoclasts after 7 days of treatment (Figures 1(a) and 1(b))
Summary
Osteoporosis is an endocrine-metabolic bone disease that is characterized by disorders in the bone remodeling process toward increased bone resorption by osteoclasts over the expenses of bone formation by osteoblasts [1]. Us, targeting osteoclast formation and differentiation via inhibiting NF-κB and MAPK signaling are an effective strategy toward preventing bone loss related diseases [10, 11]. In this context, several studies have demonstrated biological and pharmacological activities of plant-derived coumarin derivatives including antibacterial, antifungal, anti-inflammatory, antioxidative, and antitumor effects [12,13,14]. Natural coumarin derivatives including daphnetin, psoralen, and wedelolactone were reported to exhibit an inhibitory effect on osteoclastic bone resorption [15, 16]. To provide more detailed information on the effect of 5′-HA on bone metabolism, we aimed in this study to investigate the effect of 5′-HA on osteoclast differentiation of murine BM cells as well as to elucidate its molecular mechanism
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