Mechano-transduction in Osteoblastic Cells Involves Strain-regulated Estrogen Receptor alpha-mediated Control of Insulin-like Growth Factor (IGF) I Receptor Sensitivity to Ambient IGF, Leading to Phosphatidylinositol 3-Kinase/AKT-dependent Wnt/LRP5 Receptor-independent Activation of beta-Catenin Signaling
Author(s)
Type
Journal Article
Abstract
The capacity of bones to adjust their mass and architecture to withstand the loads of everyday activity derives from the ability of their resident cells to respond appropriately to the strains engendered. To elucidate the mechanisms of strain responsiveness in bone cells, we investigated in vitro the responses of primary mouse osteoblasts and UMR-106 osteoblast-like cells to a single period of dynamic strain. This stimulates a cascade of events, including activation of insulin-like growth factor I receptor (IGF-IR), phosphatidylinositol 3-kinase-mediated phosphorylation of AKT, inhibition of GSK-3β, increased activation of β-catenin, and associated lymphoid-enhancing factor/T cell factor-mediated transcription. Initiation of this pathway does not involve the Wnt/LRP5/Frizzled receptor and does not culminate in increased IGF transcription. The effect of strain on IGF-IR is mimicked by exogenous des-(1–3)IGF-I and is blocked by the IGF-IR inhibitor H1356. Inhibition of strain-related prostanoid and nitric oxide production inhibits strain-related (and basal) AKT activity, but their separate ectopic administration does not mimic it. Strain-related IGF-IR activation of AKT requires estrogen receptor α (ERα) with which IGF-1R physically associates. The ER blocker ICI 182,780 increases the concentration of des-(1–3)IGF-I necessary to activate this cascade, whereas estrogen inhibits both basal AKT activity and its activation by des-(1–3)IGF-I. These data suggest an initial cascade of strain-related events in osteoblasts in which strain activates IGF-IR, in association with ERα, so initiating phosphatidylinositol 3-kinase/AKT-dependent activation of β-catenin and altered lymphoid-enhancing factor/T cell factor transcription. This cascade requires prostanoid/nitric oxide production and is independent of Wnt/LRP5.
Date Issued
2021-01-04
Date Acceptance
2021-01-01
Citation
Journal of Biological Chemistry, 2021, 285 (12), pp.8743-8758
ISSN
0021-9258
Publisher
American Society for Biochemistry and Molecular Biology
Start Page
8743
End Page
8758
Journal / Book Title
Journal of Biological Chemistry
Volume
285
Issue
12
Copyright Statement
© 2010 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000275553700027&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
PERIOSTEAL BONE-FORMATION
MECHANICAL STRAIN
NITRIC-OXIDE
ER-ALPHA
ANABOLIC RESPONSE
ADAPTIVE RESPONSE
INDUCED APOPTOSIS
MESSENGER-RNA
BREAST-CANCER
T-ANTIGEN
Publication Status
Published
Date Publish Online
2021-01-04