PMID- 19823173
OWN - NLM
STAT- MEDLINE
DCOM- 20100202
LR  - 20230216
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Linking)
VI  - 90
IP  - 1
DP  - 2010 Jan
TI  - Rho/ROCK and MEK/ERK activation by transforming growth factor-alpha induces 
      articular cartilage degradation.
PG  - 20-30
LID - 10.1038/labinvest.2009.111 [doi]
AB  - Identification and characterization of therapeutic targets for joint conditions, 
      such as osteoarthritis (OA), is exceedingly important for addressing the 
      increasing burden of disease. Transforming growth factor-alpha (TGFalpha) is 
      upregulated by articular chondrocytes in experimentally induced and human OA. To 
      test the potential involvement of TGFalpha, which is an activator of epidermal 
      growth factor receptor (EGFR) signaling, in joint degeneration and to identify 
      signaling mechanisms mediating articular chondrocyte responses to TGFalpha, rat 
      chondrocytes and osteochondral explants were treated with TGFalpha and various 
      inhibitors of intracellular signaling pathways. Stimulation of EGFR signaling in 
      articular chondrocytes by TGFalpha resulted in the activation of RhoA/ROCK (Rho 
      kinase), MEK (MAPK/ERK kinase)/ERK (extracellular-signal-regulated kinase), PI3K 
      (phosphoinositide 3-kinase) and p38 MAPK (mitogen-activated protein kinase) 
      pathways. Modification of the chondrocyte actin cytoskeleton was stimulated by 
      TGFalpha, but inhibition of only Rho or ROCK activation prevented morphological 
      changes. TGFalpha suppressed expression of anabolic genes including Sox9, type II 
      collagen and aggrecan, which were rescued only by inhibiting MEK/ERK activation. 
      Furthermore, catabolic factor upregulation by TGFalpha was prevented by ROCK and 
      p38 MAPK inhibition, including matrix metalloproteinase-13 and tumor necrosis 
      factor-alpha, which are well known to contribute to cartilage digestion in OA. To 
      assess the ability of TGFalpha to stimulate degradation of mature articular 
      cartilage, type II collagen and aggrecan cleavage fragments were analyzed in rat 
      osteochondral explants exposed to exogenous TGFalpha. Normal articular cartilage 
      contained low levels of both cleavage fragments, but high levels were observed in 
      the cartilage treated with TGFalpha. Selective inhibition of MEK/ERK and Rho/ROCK 
      activation greatly reduced or completely prevented excess type II collagen and 
      aggrecan degradation in response to TGFalpha. These data suggest that TGFalpha is 
      a strong stimulator of cartilage degradation and that Rho/ROCK and MEK/ERK 
      signaling have critical roles in mediating these effects.
FAU - Appleton, C Thomas G
AU  - Appleton CT
AD  - CIHR Group in Skeletal Development and Remodeling, London, ON, Canada.
FAU - Usmani, Shirine E
AU  - Usmani SE
FAU - Mort, John S
AU  - Mort JS
FAU - Beier, Frank
AU  - Beier F
LA  - eng
GR  - MOP86574/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091012
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Aggrecans)
RN  - 0 (Collagen Type II)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transforming Growth Factor alpha)
RN  - EC 2.7.11.1 (rho-Associated Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
SB  - IM
MH  - Aggrecans/metabolism
MH  - Animals
MH  - Bone and Bones/metabolism
MH  - Cartilage, Articular/*metabolism/*pathology
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Chondrocytes/metabolism
MH  - Collagen Type II/metabolism
MH  - Enzyme Activation
MH  - Extracellular Matrix/drug effects/genetics
MH  - Gene Expression Regulation
MH  - Humans
MH  - Intracellular Membranes/metabolism
MH  - Male
MH  - Metabolism/genetics
MH  - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins/pharmacology
MH  - Signal Transduction/drug effects
MH  - Transforming Growth Factor alpha/*pharmacology
MH  - rho-Associated Kinases/antagonists & inhibitors/*metabolism
MH  - rhoA GTP-Binding Protein/antagonists & inhibitors/*metabolism
EDAT- 2009/10/14 06:00
MHDA- 2010/02/03 06:00
CRDT- 2009/10/14 06:00
PHST- 2009/10/14 06:00 [entrez]
PHST- 2009/10/14 06:00 [pubmed]
PHST- 2010/02/03 06:00 [medline]
AID - S0023-6837(22)02548-X [pii]
AID - 10.1038/labinvest.2009.111 [doi]
PST - ppublish
SO  - Lab Invest. 2010 Jan;90(1):20-30. doi: 10.1038/labinvest.2009.111. Epub 2009 Oct 
      12.