Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Park, Hyun-Jung; Gholam-Zadeh, Malihatosadat; Yoon, Sun‐Young; Suh, Jae-Hee; Choi, Hye‐Seon

doi:10.3390/antiox10040619

Cited by 10 publications

(7 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Park et al found that the link of c-Src to the RANK signaling cascade is essential for osteoclasts to resorb bone [23]. Moreover, in a mouse model with ovariectomy-induced bone loss, ERα suppressed the activation of c-Src in osteoclasts upon estrogen exposure and subsequently reduced bone resorption [24]. In line with the above data, we found that ICA inhibited the phosphorylation of c-Src in osteoclasts via regulating ERα, while inactivation of c-Src reversed si-ERα-promoted osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

Icariin regulates RANKL-induced osteoclast differentiation via the ERα/c-Src/RANK signaling

Yang,

Zhang,

Liao

et al. 2024

Biomed. Mater.

View full text Add to dashboard Cite

Osteoporosis (OP) is a common metabolic bone disease. Excessive osteoclastic activity significantly contributes to the development of OP. Icariin (ICA) is a flavonol glycoside derived from herbal plants and possesses curative effects on postmenopausal OP and bone fracture. This study aimed to investigate the effects of ICA on osteoclast differentiation induced by receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and the involvement of estrogen receptor α (ERα) and RANK signaling cascade in this process. RANKL was used to induce the differentiation of RAW264.7 cells to into osteoclasts. Small interfering RNA technique was used to knockdown ERα in cells. Cell counting kit-8 assay was performed to determine the cytotoxicity of ICA. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells was quantified by TRAP staining. RANKL induced the differentiation of RAW264.7 cells into osteoclasts, while ICA abolished the pro-osteoporotic effect of RANKL. Moreover, ERα knockdown abolished the effects of ICA on RANKL-induced osteoclastogenesis. Further exploration revealed that ICA inhibited the phosphorylation of c-Src in osteoclasts via regulating ERα, while inactivation of c-Src reversed ERα knockdown-promoted osteoclastogenesis. Lastly, ICA inhibited the activation of the mitogen-activated protein kinase signaling pathway and downregulated the expressions of target osteoclastogenic proteins in RANKL-treated RAW 264.7 cells, while ERα knockdown almost completely diminished the effects of ICA. ICA inhibited RANKL-induced osteoclast differentiation via regulating the ERα/c-Src/RANK signaling. These findings elucidated a novel mechanism by which ICA exerts an anti-osteoporotic effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Icariin regulates RANKL-induced osteoclast differentiation via the ERα/c-Src/RANK signaling

Yang,

Zhang,

Liao

et al. 2024

Biomed. Mater.

View full text Add to dashboard Cite

show abstract

“…35 RANKL induces the binding of c-Src and nuclear factor-κB receptor activator (RANK) to promote directly the bone resorption of osteoclasts 36 ; however, estrogen can form an ERα/ SHP2/c-Src complex in osteoclasts, which attenuates c-Src activation upon RANKL stimulation to reduce its cytoskeletal recombination signal and osteoclast proliferation. 37 It is worth mentioning that estrogen deficiency can induce oxidative stress. 38 In the bone environment, the production of oxygen free radicals will lead to the up-regulation of RANKL and downregulation of osteoprotegerin (OPG).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Berberine for Osteoporosis and its Underlying Mechanisms: A Bioinformatics, Network Pharmacology, Molecular Dynamics Simulation Study

Wang

Zhang

et al. 2022

Natural Product Communications

View full text Add to dashboard Cite

Osteoporosis is a systemic skeletal disease that can easily lead to bone fractures. Berberine has been shown to be effective in treating osteoporosis. This study was conducted to identify the potential mechanism of berberine in treating this complaint. We screened potential targets of berberine and identified the osteoporosis-related differentially expressed genes (DEGs) in the microarray dataset GSE56815. Protein–protein interaction (PPI) network construction, hub targets identification, and pathway enrichment were carried out to find the potential targets. Molecular docking and molecular dynamics studies were performed to verify the combination of berberine with its treatment-related central targets. In addition, SwissADME preliminarily evaluated the physicochemical properties of berberine. Through data mining, 23 osteoporosis-related targets of berberine were selected. PPI and module analyses suggested that AKT1, MAPK1, ESR1, AR, TP53, and PTGS2 are the core targets of berberine. Docking and molecular dynamics studies showed that berberine could stably bind to core proteins to form a protein–ligand complex. The enrichment analysis showed that the estrogen signaling pathway and thyroid hormone signaling pathway play important roles in curing osteoporosis. To sum up, berberine primarily acts on AKT1, MAPK1, ESR1, AR, TP53, and PTGS2, mainly regulating the estrogen and thyroid hormone signaling pathways to treat osteoporosis in a multi-target, multi-pathway, and multi-system manner.

show abstract

“…Osteoclasts are giant multinucleated giant cells that are mainly involved in bone resorption (Lorenzo 2017). Macrophage colony-stimulating factor (MCSF) and receptor activator of nuclear factor (NF)-kB (RANK) ligand (RANKL) play a critical role in osteoclast proliferation and differentiation (Park et al 2021). RANKL is expressed on the surface of the BMSCs, osteoblast lineage, T lymphocytes, and B lymphocytes (Eghbali-Fatourechi et al 2003).…”

Section: Effects Of Estrogen On Osteoclastsmentioning

confidence: 99%

Postmenopausal osteoporosis coexisting with sarcopenia: the role and mechanisms of estrogen

Tian

2023

Journal of Endocrinology

View full text Add to dashboard Cite

Estrogens (estradiol, estriol, and estrone) are important hormones that directly and indirectly regulate the metabolism and function of bone and skeletal muscle via estrogen receptors. Menopause causes a dramatic reduction in the concentration of estrogen in the body. This contributes to a decline in bone and skeletal muscle function, thereby resulting in osteoporosis and sarcopenia. Menopausal women often experience osteoporosis and muscle wasting, and clinicians recognize estrogen as playing an important role in these conditions, particularly in women. Bone and muscle are closely related endocrine tissues that synthesize and produce various cytokines. These bone- and muscle-derived cytokines, including interleukin-6, irisin, β-aminoisobutyric acid, osteocalcin, fibroblast growth factor-23, and sclerostin) regulate both local and distant tissues, and they mediate the crosstalk between bone and skeletal muscle. This review examines the metabolic effects of estrogen on bone and skeletal muscle and describes cytokine-mediated bone–muscle crosstalk in conditions of estrogen deficiency.

show abstract

Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Cited by 10 publications

References 36 publications

Icariin regulates RANKL-induced osteoclast differentiation via the ERα/c-Src/RANK signaling

Icariin regulates RANKL-induced osteoclast differentiation via the ERα/c-Src/RANK signaling

Therapeutic Potential of Berberine for Osteoporosis and its Underlying Mechanisms: A Bioinformatics, Network Pharmacology, Molecular Dynamics Simulation Study

Postmenopausal osteoporosis coexisting with sarcopenia: the role and mechanisms of estrogen

Contact Info

Product

Resources

About