title: Crosstalk between Wnt/β-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells.
abstract: Osteogenic differentiation from mesenchymal progenitor cells (MPCs) are initiated and regulated by a cascade of signaling events. Either Wnt/β-catenin or estrogen signaling pathway has been shown to play an important role in regulating skeletal development and maintaining adult tissue homeostasis. Here, we investigate the potential crosstalk and synergy of these two signaling pathways in regulating osteogenic differentiation of MPCs. We find that the activation of estrogen receptor (ER) signaling by estradiol (E2) or exogenously expressed ERα in MPCs synergistically enhances Wnt3A-induced early and late osteogenic markers, as well as matrix mineralization. The E2 or ERα-mediated synergy can be effectively blocked by ERα antagonist tamoxifen. E2 stimulation can enhance endochondral ossification of Wnt3A-transduced mouse fetal limb explants. Furthermore, exogenously expressed ERα significantly enhances the maturity and mineralization of Wnt3A-induced subcutaneous and intramuscular ectopic bone formation. Mechanistically, we demonstrate that E2 does not exert any detectable effect on β-catenin/Tcf reporter activity. However, ERα expression is up-regulated within the first 48h in AdWnt3A-transduced MPCs, whereas ERβ expression is significantly inhibited within 24h. Moreover, the key enzyme for the biosynthesis of estrogens aromatase is modulated by Wnt3A in a biphasic manner, up-regulated at 24h but reduced after 48h. Our results demonstrate that, while ER signaling acts synergistically with Wnt3A in promoting osteogenic differentiation, Wnt3A may crosstalk with ER signaling by up-regulating ERα expression and down-regulating ERβ expression in MPCs. Thus, the signaling crosstalk and synergy between these two pathways should be further explored as a potential therapeutic approach to combating bone and skeletal disorders, such as fracture healing and osteoporosis.
authors: Department of Geriatrics, Xinhua Hospital of Shanghai Jiaotong University, School of Medicine, Shanghai, China ; Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois, United States of America.
authors: Yanhong
authors: Y
authors: Gao
authors: Enyi
authors: E
authors: Huang
authors: Hongmei
authors: H
authors: Zhang
authors: Jinhua
authors: J
authors: Wang
authors: Ningning
authors: N
authors: Wu
authors: Xian
authors: X
authors: Chen
authors: Ning
authors: N
authors: Wang
authors: Sheng
authors: S
authors: Wen
authors: Guoxin
authors: G
authors: Nan
authors: Fang
authors: F
authors: Deng
authors: Zhan
authors: Z
authors: Liao
authors: Di
authors: D
authors: Wu
authors: Bosi
authors: B
authors: Zhang
authors: Junhui
authors: J
authors: Zhang
authors: Rex C
authors: RC
authors: Haydon
authors: Hue H
authors: HH
authors: Luu
authors: Lewis L
authors: LL
authors: Shi
authors: Tong-Chuan
authors: TC
authors: He
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D004958:Estradiol