Estrogen Decreases Cytoskeletal Organization by Forming an ER alpha/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice
- 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 말리하토사닷; 박현정; 윤선영; 서재희; 최혜선
- Issued Date
- 2021
- Type
- Article
- Keyword
- estrogen (E2); Erα; osteoclast; actin ring formation; non-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
-
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