Dehydrodiconiferyl Alcohol Inhibits Osteoclast Differentiation and Ovariectomy-Induced Bone Loss through Acting as an Estrogen Receptor Agonist

Abstract

Estrogen deficiency after menopause increases bone loss by activating RANKL-induced osteoclast differentiation. Dehydrodiconiferyl alcohol (DHCA), a lignan originally isolated from Cucurbita moschata, has been thought to be a phytoestrogen based on its structure. In this study, we tested whether DHCA could affect RANKL-induced osteoclastogenesis in vitro and ovariectomy-induced bone loss in vivo. In RAW264.7 cells, DHCA inhibited RANKL-induced differentiation of osteoclasts. Consistently, expression of the six osteoclastogenic genes induced by RANKL was down-regulated. DHCA was also shown to suppress the NF-κB and p38 MAPK signaling pathways by activating AMPK. Data from transient transfection assays suggested that DHCA might activate the estrogen receptor signaling pathway. Effects of DHCA on RANKL-induced osteoclastogenesis were reduced when cells were treated with specific siRNA to ERα, but not to ERβ. Interestingly, DHCA was predicted from molecular docking simulation to bind to both ERα and ERβ. Indeed, data from an estrogen receptor competition assay revealed that DHCA acted as an agonist on both estrogen receptors. In the ovariectomized (Ovx) mouse model, DHCA prevented Ovx-induced bone loss by inhibiting osteoclastogenesis. Taken together, our results suggest that DHCA may be developed as an efficient therapeutic for osteoporosis by regulating osteoclastogenesis through its estrogenic effects.

Isorhamnetin attenuates osteoarthritis by inhibiting osteoclastogenesis and protecting chondrocytes through modulating reactive oxygen species homeostasis

“…MAPK is in the serine‐threonine protein kinase family that is involved in cell viability, differentiation, apoptosis, inflammation and innate immunity . The most studied proteins of the MAPK pathway are ERK, JNK and p38 kinases, which can respond to extracellular stimuli including growth factors, heat shock proteins and pro‐inflammatory cytokines . Specific inhibitors of JNK, p38 and ERK can inhibit RANKL‐stimulated osteoclast differentiation, indicating that MAPK is important for osteoclast activation and bone resorption .…”

Muscone Ameliorates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κb Ligand-Induced Osteoclastogenesis by Suppressing TNF Receptor–Associated Factor 6-Mediated Signaling Pathways

“…After menopause, estrogen deficiency leads to the higher levels of RANKL and proinflammatory factors, including IL-6 and TNF-a (Sun et al, 2018). The over-activation of RANKL signaling pathways recruits the RANK/TRAF6 association and thus promotes the reproduction of osteoclasts Lee et al, 2018). As a result, it is a potential therapeutic target for PMOP via inhibiting osteoclastogenesis.…”

In Silico Identification and Biological Evaluation of Antioxidant Food Components Endowed with Human Carbonic Anhydrase IX and XII Inhibition

“…In the literature, it was found to exert anti- Helicobacter pylori [ 59 ], antiadipogenic [ 60 ], and antioxidant effects [ 61 ]. Recently, Lee et al reported that (-)-dehydrodiconiferyl alcohol suppresses the p38 MAPK and NF-κB signaling pathways in RAW 264.7 cells and acts as an estrogen receptor agonist [ 62 ]. Moreover, it exerts anti-inflammatory activity by regulating key molecules involved in inflammation and oxidative stress, such as pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and mediators (iNOS, COX-2, and ROS) [ 63 ].…”