PMID- 15801908
OWN - NLM
STAT- MEDLINE
DCOM- 20051104
LR  - 20220331
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 389
IP  - Pt 3
DP  - 2005 Aug 1
TI  - IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation 
      of the PI 3-kinase pathway but not ERK MAPK.
PG  - 723-9
AB  - The IGF-I (insulin-like growth factor-I) signalling pathway responsible for 
      regulation of proteoglycan synthesis in chondrocytes has not been defined and is 
      the focus of the present study. Chondrocytes isolated from normal human articular 
      cartilage were stimulated with IGF-I in monolayer culture or in suspension in 
      alginate. IGF-I activated members of both the PI3K (phosphoinositide 3-kinase) 
      pathway and the ERK (extracellular-signal-regulated kinase)/MAPK 
      (mitogen-activated protein kinase) pathway. The PI3K inhibitors LY294002 and 
      wortmannin blocked IGF-I-stimulated Akt phosphorylation without blocking ERK 
      phosphorylation and this was associated with complete inhibition of proteoglycan 
      synthesis. A decrease in IGF-I-stimulated proteoglycan synthesis was also 
      observed upon inhibition of mTOR (mammalian target of rapamycin) and p70S6 
      kinase, both of which are downstream of Akt. The MEK (MAPK/ERK kinase) inhibitors 
      PD98059 and U0126 blocked IGF-I-stimulated ERK phosphorylation but did not block 
      the phosphorylation of Akt and did not decrease proteoglycan synthesis. Instead, 
      in alginate- cultured chondrocytes, the MEK inhibitors increased IGF-I-stimulated 
      proteoglycan synthesis when compared with cells treated with IGF-I alone. This is 
      the first study to demonstrate that IGF-I stimulation of the PI3K signalling 
      pathway is responsible for the ability of IGF-I to increase proteoglycan 
      synthesis. Although IGF-I also activates the ERK/MAPK pathway, ERK activity is 
      not required for proteoglycan synthesis and may serve as a negative regulator.
FAU - Starkman, Bela G
AU  - Starkman BG
AD  - Department of Biochemistry, Rush Medical College of Rush University Medical 
      Center, Chicago, IL 60612, USA.
FAU - Cravero, John D
AU  - Cravero JD
FAU - Delcarlo, Marcello
AU  - Delcarlo M
FAU - Loeser, Richard F
AU  - Loeser RF
LA  - eng
GR  - R01 AG016697/AG/NIA NIH HHS/United States
GR  - R01 AG16697/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proteoglycans)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chondrocytes/drug effects/*metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/*metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Insulin-Like Growth Factor I/*physiology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Proteoglycans/*biosynthesis
MH  - Signal Transduction
PMC - PMC1180722
EDAT- 2005/04/02 09:00
MHDA- 2005/11/05 09:00
PMCR- 2006/02/01
CRDT- 2005/04/02 09:00
PHST- 2005/04/02 09:00 [pubmed]
PHST- 2005/11/05 09:00 [medline]
PHST- 2005/04/02 09:00 [entrez]
PHST- 2006/02/01 00:00 [pmc-release]
AID - BJ20041636 [pii]
AID - bj3890723 [pii]
AID - 10.1042/BJ20041636 [doi]
PST - ppublish
SO  - Biochem J. 2005 Aug 1;389(Pt 3):723-9. doi: 10.1042/BJ20041636.