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The Dibenzyl Isoquinoline Alkaloid Berbamine Ameliorates Osteoporosis by Inhibiting Bone Resorption.

ABSTRACT: Postmenopausal osteoporosis (PMOP) is a kind of primary osteoporosis that is characterized by decreased bone density and strength. Berbamine is a nonbasic quaternary benzylisoquinoline plant alkaloid that has been widely used in the clinic to treat leukopenia in China. We found that berbamine inhibited RANKL-induced osteoclastogenesis of bone marrow-derived macrophages (BMMs) in vitro, which mainly occurred in the middle phase and late phase. The gene and protein expression levels of osteoclast-related molecules, including CTSK, MMP-9, NFATc1, CD44 and DC-STAMP, were also downregulated by berbamine. In vivo, we treated PMOP mice with berbamine for 8 weeks and found that the extent of osteoporosis was alleviated significantly according to micro-CT scanning, hematoxylin-eosin staining, DC-STAMP immunohistochemical staining and TRAP immunohistochemical staining in the distal femurs of the mice. Our findings demonstrate that berbamine has an inhibitory effect on the osteoclastogenesis of BMMs and can prevent bone loss after ovariectomy in vivo. This study provides evidence that berbamine is a potential drug for the prevention and treatment of PMOP.

SUBMITTER: Zhang C

PROVIDER: S-EPMC9159364 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The Dibenzyl Isoquinoline Alkaloid Berbamine Ameliorates Osteoporosis by Inhibiting Bone Resorption.

Zhang Chongjing C Zhong Zeyuan Z Sang Weicong W Ghorbani Farnaz F Ghalandari Behafarid B Mohamadali Marjan M Irani Shiva S Qian Zhi Z Yi Chengqing C Yu Baoqing B

Frontiers in endocrinology 20220518

Postmenopausal osteoporosis (PMOP) is a kind of primary osteoporosis that is characterized by decreased bone density and strength. Berbamine is a nonbasic quaternary benzylisoquinoline plant alkaloid that has been widely used in the clinic to treat leukopenia in China. We found that berbamine inhibited RANKL-induced osteoclastogenesis of bone marrow-derived macrophages (BMMs) <i>in vitro</i>, which mainly occurred in the middle phase and late phase. The gene and protein expression levels of oste ...[more]

PMID: 35663327

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Project description:Dysregulation of osteoclast-osteoblast balance, resulting in abnormal bone remodeling, is responsible for postmenopausal osteoporosis (PMOP) or other secondary forms of osteoporosis. We demonstrated that dictamnine (DIC), a novel RANKL-targeted furoquinoline alkaloid, inhibits osteoclastogenesis by facilitating the activities of reactive oxygen species (ROS), NF-κB, and NFATc1 in vitro and prevents the development of OVX-induced osteoporosis mouse models in vivo. Methods. The docking mechanism of DIC and RANKL was initially identified by protein-ligand molecular docking. RNA sequencing was performed and analyzed to reveal the potential mechanism and signaling pathway of the antiosteoporosis effects of DIC. To verify the sequencing results, we examined the impact of DIC on RANKL-induced osteoclast differentiation, bone resorption, F-actin ring production, ROS generation, and NF-κB activation in osteoclasts in vitro. Moreover, a luciferase assay was performed to determine the binding and transcriptional activity of Nrf2 and NF-κB. The in vivo efficacy of DIC was assessed with an ovariectomy- (OVX-) induced osteoporosis model, which was analyzed using micro-CT and bone histomorphometry. Results. The molecular docking results indicated that DIC could bind particularly to RANKL. RNA-seq confirmed that DIC could regulate the osteoclast-related pathway. DIC suppressed osteoclastogenesis, bone resorption, F-actin belt formation, osteoclast-specific gene expression, and ROS activity by preventing NFATc1 expression and affecting NF-κB signaling pathways in vitro. The luciferase assay showed that DIC not only suppressed the activity of Nrf2 but also contributed to the combination of Nrf2 and NF-κB. Our in vivo study indicated that DIC protects against OVX-induced osteoporosis and preserves bone volume by inhibiting osteoclast activity and function. Conclusions. DIC can ameliorate osteoclast formation and OVX-induced osteoporosis and therefore is a potential therapeutic treatment for osteoporosis.

Project description:Bone marrow adipose tissue (BMAT) accrues in osteoporosis, whereas its contribution to the progression of bone resorption remains insufficiently understood. To understand the mechanisms that promote BMAT expansion in osteoporosis, in the present study, we performed extensive analysis of the spatiotemporal pattern of BMAT expansion during the progression of bone resorption in TgRANKL transgenic mouse models of osteoporosis expressing human RANKL (receptor activator of nuclear factor-κB ligand). Our results showed that TgRANKL mice of both sexes developed dramatically increased BMAT expansion compared to wild-type (WT) littermates, that was analogous to the levels of RANKL expression and the severity of the bone loss phenotype. BMAT was formed at close proximity to areas undergoing active bone remodelling and bone resorption, whereas bone resorption preceded BMAT development. Expression analysis in bone fractions demonstrated that BMAT constitutes a major source for RANKL production. Ex vivo analysis of isolated bone marrow stromal cells from TgRANKL mice showed an increased adipogenic differentiation capacity compared to WT, while osteoclast supernatants further exaggerated adipogenesis, supporting a critical role of the osteoclast-derived secretome in the differentiation of bone marrow adipocytes. Furthermore, the effectiveness of an antiosteoporosis treatment in BMAT development was investigated upon treatment of TgRANKL models with the bisphosphonate alendronate. Notably, alendronate effectively improved bone mass and attenuated BMAT expansion, indicating a possible involvement of osteoclasts and bone resorption in BMAT development. On the contrary, inhibition of BMAT with PPARγ antagonists (GW9662 or BADGE) effectively ameliorated BMAT expansion but failed to reverse the osteoporotic phenotype of TgRANKL mice. Overall, our data demonstrate that TgRANKL mice constitute unique genetic mouse models for investigating the pathogenic mechanisms that regulate the development and expansion of BMAT in osteolytic diseases.

Dataset Information

The Dibenzyl Isoquinoline Alkaloid Berbamine Ameliorates Osteoporosis by Inhibiting Bone Resorption.

Publications

The Dibenzyl Isoquinoline Alkaloid Berbamine Ameliorates Osteoporosis by Inhibiting Bone Resorption.

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