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

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Abstract
Loss of ovarian function is closely related to estrogen (E-2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E-2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E-2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E-2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ER alpha) antagonist, augmented the OC size. ER alpha was found in plasma membranes and E-2/ER alpha signaling affected receptor activator of nuclear factor kappa B ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E-2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ER alpha formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E-2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p-Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E-2/ER alpha signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E-2-binding to ER alpha forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.
Author(s)
골람 자데 말리하토사닷박현정윤선영서재희최혜선
Issued Date
2021
Type
Article
Keyword
estrogen (E2)Erαosteoclastactin ring formationnon-genomic signal
DOI
10.3390/antiox10040619
URI
https://oak.ulsan.ac.kr/handle/2021.oak/9566
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_5268c8809a63442881a29e4f5a303fe4&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Estrogen%20Decreases%20Cytoskeletal%20Organization%20by%20Forming%20an%20ER%20alpha%2FSHP2%2Fc-Src%20Complex%20in%20Osteoclasts%20to%20Protect%20against%20Ovariectomy-Induced%20Bone%20Loss%20in%20Mice&offset=0&pcAvailability=true
Publisher
ANTIOXIDANTS
Location
스위스
Language
영어
ISSN
2076-3921
Citation Volume
10
Citation Number
4
Citation Start Page
619
Citation End Page
619
Appears in Collections:
Natural Science > Biological Sciences
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