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High Doses of Bupleurum falcatum Partially Prevents Estrogen Deficiency-Induced Bone Loss With Anti-osteoclastogenic Activity Due to Enhanced iNOS/NO Signaling.

ABSTRACT: Background and Objective: Bupleurum falcatum (BF) extract, a natural product with anti-inflammatory properties, has been traditionally used to treat menopausal symptoms, but its role in osteoporosis, another serious health concern of menopausal women, remains unknown. Here we investigated whether and how BF prevents estrogen deficiency-induced bone loss using both in vitro and in vivo models. Methods: Female Sprague-Dawley rats were ovariectomized (OVX) and subjected to oral BF treatment daily for 8 weeks. Additionally, pre-osteoclastic RAW 264.7 cells were employed to evaluate the effects of BF and its underlying mechanism on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in vitro. Results: A high dose of BF partially prevented ovariectomy (OVX)-induced bone loss and reduced the levels of tartrate-resistant acid phosphatase (TRAP) in serum and osteoclast numbers in femurs of OVX rats. Furthermore, BF clearly inhibited RANKL-induced osteoclast differentiation and bone resorption activity in RAW 264.7 cells. BF also inhibited the osteoclastogenic transcription factors c-Fos and nuclear factor of activated T cells c1 (NFATc1) and, consequently, downregulated the expression of osteoclast marker genes. Moreover, BF upregulated interferon-? (IFN-?)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) signaling, even though it had no impact on mitogen-activated protein kinases (MAPK) or NF-?B. The inhibition of osteoclast formation by BF was abrogated by iNOS-specific inhibitors. Consistent with cellular studies, BF upregulated iNOS protein expression in femurs from OVX rats. Conclusion: Taken together, our results indicate that BF partially prevented estrogen deficiency-induced bone loss with anti-osteoclastogenic activity potentially due to enhanced iNOS/NO signaling.

SUBMITTER: Yeom M

PROVIDER: S-EPMC6262412 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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High Doses of Bupleurum falcatum Partially Prevents Estrogen Deficiency-Induced Bone Loss With Anti-osteoclastogenic Activity Due to Enhanced iNOS/NO Signaling.

Yeom Mijung M Kim Eun-Young EY Kim Jae-Hyun JH Jung Hyuk-Sang HS Sohn Youngjoo Y

Frontiers in pharmacology 20181116

Background and Objective: Bupleurum falcatum (BF) extract, a natural product with anti-inflammatory properties, has been traditionally used to treat menopausal symptoms, but its role in osteoporosis, another serious health concern of menopausal women, remains unknown. Here we investigated whether and how BF prevents estrogen deficiency-induced bone loss using both in vitro and in vivo models. Methods: Female Sprague-Dawley rats were ovariectomized (OVX) and sub ...[more]

PMID: 30524278

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Project description:Recent in vitro studies have revealed that the mechanobiological responses of osteoblasts and osteocytes are fundamentally impaired during estrogen deficiency. However, these two-dimensional (2D) cell culture studies do not account for in vivo biophysical cues. Thus, the objectives of this study are to (1) develop a three-dimensional (3D) osteoblast and osteocyte model integrated into a bioreactor and (2) apply this model to investigate whether estrogen deficiency leads to changes in osteoblast to osteocyte transition, mechanosensation, mineralization, and paracrine signaling associated with bone resorption by osteoclasts. MC3T3-E1s were expanded in media supplemented with estrogen (17?-estradiol). These cells were encapsulated in gelatin-mtgase before culture in (1) continued estrogen (E) or (2) no further estrogen supplementation. Constructs were placed in gas permeable and water impermeable cell culture bags and maintained at 5% CO2 and 37°C. These bags were either mechanically stimulated in a custom hydrostatic pressure (HP) bioreactor or maintained under static conditions (control). We report that osteocyte differentiation, characterized by the presence of dendrites and staining for osteocyte marker dentin matrix acidic phosphoprotein 1 (DMP1), was significantly greater under estrogen withdrawal (EW) compared to under continuous estrogen treatment (day 21). Mineralization [bone sialoprotein (BSP), osteopontin (OPN), alkaline phosphatase (ALP), calcium] and gene expression associated with paracrine signaling for osteoclastogenesis [receptor activator of nuclear factor kappa-? ligand (RANKL)/osteoprotegerin OPG ratio] were significantly increased in estrogen deficient and mechanically stimulated cells. Interestingly, BSP and DMP-1 were also increased at day 1 and day 21, respectively, which play a role in regulation of biomineralization. Furthermore, the increase in pro-osteoclastogenic signaling may be explained by altered mechanoresponsiveness of osteoblasts or osteocytes during EW. These findings highlight the impact of estrogen deficiency on bone cell function and provide a novel in vitro model to investigate the mechanisms underpinning changes in bone cells after estrogen deficiency.

Dataset Information

High Doses of Bupleurum falcatum Partially Prevents Estrogen Deficiency-Induced Bone Loss With Anti-osteoclastogenic Activity Due to Enhanced iNOS/NO Signaling.

Publications

High Doses of <i>Bupleurum falcatum</i> Partially Prevents Estrogen Deficiency-Induced Bone Loss With Anti-osteoclastogenic Activity Due to Enhanced iNOS/NO Signaling.

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