Endocrine Abstracts (2006) 11 P19

The effect of ceramide on IGF-1 induced proliferation in growth plate chondrocytes

VE MacRae1, SF Ahmed2 & C Farquharson1


1Roslin Institute, Midlothian, United Kingdom; 2Royal Hospital For Sick Children, Glasgow, United Kingdom.


Abnormal growth patterns are commonly observed in children suffering from chronic inflammatory diseases. These disorders are associated with the increased production of pro-inflammatory cytokines, which inhibit growth plate chondrocyte dynamics. Ceramide, a sphingosine-based lipid second messenger, mediates many of the actions of pro-inflammatory cytokines. Ceramide inhibits IGF-1 signalling and induces apoptosis in numerous cell types. This study determined the effects of C2-ceramide (C2-c) (40 μM, 25 μM, 10 μM), a cell permeable ceramide analogue, on murine growth plate chondrocytes, using the ATDC5 chondrogenic cell line and cultured fetal metatarsals. In ATDC5 cells, C2-c at 40 μM and 25 μM significantly induced apoptosis (63%; P<0.05 and x%) and significantly reduced proliferation (62%; P<0.05 and x%). C2-cat 40 μM significantly reduced fetal metatarsal growth (62%; P<0.05). The effect of C2-c on IGF-1 induced proliferation was examined. In ATDC5 cells, in the presence of IGF-1 (24 h, 100 ng/ml), ceramide (25 μM) induced a 68% reduction in proliferation (P<0.001). However, in the absence of IGF-1, ceramide induced a comparable 61% decrease (P<0.001). C2-c (40 μM) induced the same 31% reduction in metatarsal growth both in the presence and absence of IGF-1 (8 d, 100 ng/ml) (both P<0.001). Therefore, C2-c does not appear to specifically inhibit the pro-proliferative effects of exogenous IGF-1.The effect of C2-c on endogenous IGF-1 induced proliferation was also examined, using AG1024, an IGF-1R and IR blocker (10 μM). In the absence of exogenous IGF-1, AG1024 significantly reduced proliferation (28%, P<0.001). C2-c (25 μM) significantly reduced proliferation compared to AG1024 treatment (55%, P<0.001). C2-c and AG1024 in combination further reduced proliferation compared to C2-c alone (46% P<0.01). Further studies are required to confirm whether the inhibitory effects of pro-inflammatory cytokines in growth plate chondrocytes are mediated through ceramide, influencing the growth of children with inflammatory diseases through a local effect at the growth plate.

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