Articular chondrocytes from aging rats respond poorly to insulin-like growth factor-1: an altered signaling pathway.
This study investigates the effect of insulin-like growth factor-1 (IGF-1) and phorbol 12-myrystate 13-acetate (PMA) on 3H-thymidine, 35SO(4) and 3H -glycine incorporations, adenosine 3':5'-cyclic monophosphate (cAMP) production and protein kinase C (PKC) activation in cultured rat articular chondrocyte monolayers (RACM) derived from animals of different ages. It was found that IGF-1 stimulates all these cellular functions in cultures derived from all age groups in a concentration dependent manner, although the cells from 14-month old animals responded poorly. IGF-1 also induces in cells from 1-month old rats an increase in the expression of mRNAs specific for aggrecan and type II collagen molecules as shown with RT-PCR. These effects are mediated via IGF-1 interaction with specific receptors because the monoclonal antibody against the receptor protein suppresses more than 60% of the ligand-induced DNA synthesis. PMA, a direct PKC activator, potentiated IGF-1-induced effects in all cells but much more strongly in cells from young than in cells from 14-month old animals. The age-related failure of RACM to respond adequately to IGF-1 was correlated with a decrease in IGF-1-induced cAMP production, and IGF-1-induced and PMA-induced PKC activations. These results show that IGF-1 regulates the synthesis of DNA, proteoglycans (PG) and collagen II at the level of transcription and suggest that the reduced response of cell monolayers derived from 14-month old rats to IGF-1 is probably due to a failure of old cells to adequately transduce IGF-1 receptor-generated downstream signaling.
Messai
H
H
U-349 INSERM, 6 rue Guy-Patin, 75475, Cedex 10, Paris, France.
Duchossoy
Y
Y
Khatib
A M
AM
Panasyuk
A
A
Mitrovic
D R
DR
D053674:Aggrecans; D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000502:physiology; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D000242:Cyclic AMP / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins; D015870:Gene Expression / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D037181:Lectins, C-Type; D008297:Male; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
C508321:Acan protein, rat; D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D004247:DNA; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine