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 H-3-thymidine. (SO4)-S-35 and H-3 -glycine incorporations, adenosine 3':5'-cyclic monophosphate (cAMP) pr oduction and protein kinase C (PKC) activation in cultured rat articular ch ondrocyte monolayers (RACM) derived from animals of different ages. It was found that IGF-1 stimulates all these cellular functions in cultures derive d from all age groups in a concentration dependent manner: although the cel ls 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 a ggrecan and type II collagen molecules as shown with RT-PCR. These effects are mediated via IGF-1 interaction with specific receptors because the mono clonal antibody against the receptor protein suppresses more than 60% of th e ligand-induced DNA synthesis. PMA, a direct PKC activator, potentiated IG F-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 t o respond adequately to IGF-1 was correlated with a decrease in IGF-1-induc ed cAMP production, and IGF-1-induced and PMA-induced PKC activations. Thes e results show that IGF-1 regulates the synthesis of DNA, proteoglycans (PG ) and collagen II at the level of transcription and suggest that the reduce d response of cell monolayers derived from 14-month old rats to IGF-1 is pr obably due to a failure of old cells to adequately transduce IGF-1 receptor -generated downstream signaling. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.