Abstract
Eudebeiolide B is a eudesmane-type sesquiterpenoid compound isolated from Salvia plebeia R. Br., and little is known about its biological activity. In this study, we investigated the effects of eudebeiolide B on osteoblast differentiation, receptor activator nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in vitro and ovariectomy-induced bone loss in vivo. Eudebeiolide B induced the expression of alkaline phosphatase (ALP) and calcium accumulation during MC3T3-E1 osteoblast differentiation. In mouse bone marrow macrophages (BMMs), eudebeiolide B suppressed RANKL-induced osteoclast differentiation of BMMs and bone resorption. Eudebeiolide B downregulated the expression of nuclear factor of activated T-cells 1 (NFATc1) and c-fos, transcription factors induced by RANKL. Moreover, eudebeiolide B attenuated the RANKL-induced expression of osteoclastogenesis-related genes, including cathepsin K (Ctsk), matrix metalloproteinase 9 (MMP9) and dendrocyte expressed seven transmembrane protein (DC-STAMP). Regarding the molecular mechanism, eudebeiolide B inhibited the phosphorylation of Akt and NF-κB p65. In addition, it downregulated the expression of cAMP response element-binding protein (CREB), Bruton’s tyrosine kinase (Btk) and phospholipase Cγ2 (PLCγ2) in RANKL-induced calcium signaling. In an ovariectomized (OVX) mouse model, intragastric injection of eudebeiolide B prevented OVX-induced bone loss, as shown by bone mineral density and contents, microarchitecture parameters and serum levels of bone turnover markers. Eudebeiolide B not only promoted osteoblast differentiation but inhibited RANKL-induced osteoclastogenesis through calcium signaling and prevented OVX-induced bone loss. Therefore, eudebeiolide B may be a new therapeutic agent for osteoclast-related diseases, including osteoporosis, rheumatoid arthritis and periodontitis.
Highlights
Osteoporosis is characterized by a weak bone structure and a decrease in bone density; it has become a major health problem [1]
One of the major downstream signals involved in osteoclast differentiation is calcium signaling, which is mediated by immunoreceptor tyrosine-based activation motif (ITAM)-bearing adaptor molecules, such as Fc receptor common γ subunit (FcRγ) and DNAX-activating protein 12 (DAP12) [8,9,10,11]
Specific antibodies against p-extracellular-regulated kinase (ERK) (Tyr202/204), p-P38, p-Jun N-terminal kinase (JNK) (Tyr1007/1008), p-Akt, p-cAMP response element-binding protein (CREB), p-phospholipase Cγ2 (PLCγ2) (Tyr759), p-Bruton’s tyrosine kinase (Btk) (Tyr223), NFATc1 and c-Fos were obtained from Cell Signaling Technology (Boston, MA, USA)
Summary
Osteoporosis is characterized by a weak bone structure and a decrease in bone density; it has become a major health problem [1]. Macrophage colony-stimulating factor (M-CSF) and receptor activator nuclear factor-κB (NF-κB) ligand (RANKL) are the two major factors involved in osteoclast differentiation. M-CSF induces the proliferation and survival of osteoclast precursor cells, whereas RANKL stimulates osteoclast differentiation and activation. RANKL expressed in activated osteoblasts binds its receptor, RANK, which is expressed on the surface of osteoclast precursors, and activates multiple downstream signaling pathways [6]. One of the major downstream signals involved in osteoclast differentiation is calcium signaling, which is mediated by immunoreceptor tyrosine-based activation motif (ITAM)-bearing adaptor molecules, such as Fc receptor common γ subunit (FcRγ) and DNAX-activating protein 12 (DAP12) [8,9,10,11]. CREB and NFATc1 induce the expression of osteoclast-specific genes such as tartrate-resistant acid phosphatase (TRAP), MMP9, NFATc1 and Cstk [13,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
