PMID- 25002119
OWN - NLM
STAT- MEDLINE
DCOM- 20150102
LR  - 20211203
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 28
IP  - 10
DP  - 2014 Oct
TI  - Mechanical activation of mammalian target of rapamycin pathway is required for 
      cartilage development.
PG  - 4470-81
LID - 10.1096/fj.14-252783 [doi]
AB  - Mechanical stress regulates development by modulating cell signaling and gene 
      expression. However, the cytoplasmic components mediating mechanotransduction 
      remain unclear. In this study, elimination of muscle contraction during chicken 
      embryonic development resulted in a reduction in the activity of mammalian target 
      of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR 
      activity led to significant inhibition of chondrocyte proliferation, cartilage 
      tissue growth, and expression of chondrogenic genes, including Indian hedgehog 
      (Ihh), a critical mediator of mechanotransduction. Conversely, cyclic loading (1 
      Hz, 5% matrix deformation) of embryonic chicken growth plate chondrocytes in 
      3-dimensional (3D) collagen scaffolding induced sustained activation of mTOR. 
      Mechanical activation of mTOR occurred in serum-free medium, indicating that it 
      is independent of growth factor or nutrients. Treatment of chondrocytes with Rapa 
      abolished mechanical activation of cell proliferation and Ihh gene expression. 
      Cyclic loading of chondroprogenitor cells deficient in SH2-containing protein 
      tyrosine phosphatase 2 (Shp2) further enhanced mechanical activation of mTOR, 
      cell proliferation, and chondrogenic gene expression. This result suggests that 
      Shp2 is an antagonist of mechanotransduction through inhibition of mTOR activity. 
      Our data demonstrate that mechanical activation of mTOR is necessary for cell 
      proliferation, chondrogenesis, and cartilage growth during bone development, and 
      that mTOR is an essential mechanotransduction component modulated by Shp2 in the 
      cytoplasm.
CI  - (c) FASEB.
FAU - Guan, Yingjie
AU  - Guan Y
AD  - Cell and Molecular Biology Laboratory, Department of Orthopaedics, Alpert Medical 
      School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA; 
      and.
FAU - Yang, Xu
AU  - Yang X
AD  - Cell and Molecular Biology Laboratory, Department of Orthopaedics, Alpert Medical 
      School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA; 
      and Department of Orthopaedics, Affiliated Hospital of Medical College of Qingdao 
      University, Qingdao, China.
FAU - Yang, Wentian
AU  - Yang W
AD  - Cell and Molecular Biology Laboratory, Department of Orthopaedics, Alpert Medical 
      School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA; 
      and.
FAU - Charbonneau, Cherie
AU  - Charbonneau C
AD  - Cell and Molecular Biology Laboratory, Department of Orthopaedics, Alpert Medical 
      School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA; 
      and.
FAU - Chen, Qian
AU  - Chen Q
AD  - Cell and Molecular Biology Laboratory, Department of Orthopaedics, Alpert Medical 
      School of Brown University/Rhode Island Hospital, Providence, Rhode Island, USA; 
      and qian_chen@brown.edu.
LA  - eng
GR  - P20 GM104937/GM/NIGMS NIH HHS/United States
GR  - R01 AG017021/AG/NIA NIH HHS/United States
GR  - GM104937/GM/NIGMS NIH HHS/United States
GR  - AG017021/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140702
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Hedgehog Proteins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Animals
MH  - Cartilage/embryology/*metabolism
MH  - Cell Proliferation
MH  - Chick Embryo
MH  - Chondrocytes/cytology/*metabolism/physiology
MH  - *Chondrogenesis
MH  - Hedgehog Proteins/genetics/metabolism
MH  - *Mechanotransduction, Cellular
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/metabolism
MH  - Stress, Mechanical
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
PMC - PMC4202102
OTO - NOTNLM
OT  - Shp2
OT  - chondrocyte
OT  - mTOR
OT  - mechanotransduction
EDAT- 2014/07/09 06:00
MHDA- 2015/01/03 06:00
PMCR- 2015/10/01
CRDT- 2014/07/09 06:00
PHST- 2014/07/09 06:00 [entrez]
PHST- 2014/07/09 06:00 [pubmed]
PHST- 2015/01/03 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - fj.14-252783 [pii]
AID - 14-252783 [pii]
AID - 10.1096/fj.14-252783 [doi]
PST - ppublish
SO  - FASEB J. 2014 Oct;28(10):4470-81. doi: 10.1096/fj.14-252783. Epub 2014 Jul 2.