Mechanisms of Ageing and Development 115 (2000) 21–37 Articular chondrocytes from aging rats respond poorly to insulin-like growth factor-1: an altered signaling pathway Habib Messai a , Yann Duchossoy a , Abdel-Majid Khatib a , Andrei Panasyuk a,b , Dragoslav R. Mitrovic a, * a U-349 INSERM, 6 rue Guy -Patin, 75475 Paris, Cedex 10, France b Institute of Rheumatology, AMS, Moscow, Russia Received 26 November 1999; received in revised form 15 February 2000; accepted 21 February 2000 Abstract This study investigates the effect of insulin-like growth factor-1 (IGF-1) and phorbol 12-myrystate 13-acetate (PMA) on 3 H-thymidine, 35 SO 4 and 3 H -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-in- duced 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 www.elsevier.com/locate/mechagedev * Corresponding author. Tel.: +33-1-49956447; fax: +33-1-49958452. E-mail address: dragoslav.mitrovic@lrb.ap-hop-par (D.R. Mitrovic) 0047-6374/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 4 7 - 6 3 7 4 ( 0 0 ) 0 0 1 0 7 - X