Transient chondrocyte nonresponsiveness to insulin-like growth factor-1 upon H2O2 exposure is not related to IGF receptor damage.
We have shown that for anatomically intact murine cartilage, insulin-like growth factor-1 (IGF-1) is the major anabolic stimulus. Using an experimental arthritis model, we found that cartilage from an arthritic joint could not be stimulated in vitro with IGF-1. This nonresponsiveness was not caused by a generalized disturbance of chondrocyte metabolism since forskolin, an activator of adenylate cyclase, could stimulate cartilage from arthritic joints. To investigate whether hydrogen peroxide may cause IGF-1 nonresponsiveness, we exposed normal murine cartilage to H2O2 in vitro as well as in vivo. We found that cartilage, in which chondrocyte proteoglycan synthesis was inhibited due to H2O2 action in vitro, showed a normal response to IGF-1 after 24-h tissue culture. A time dependent but full recovery was found. In contrast, cartilage which was longterm exposed to H2O2 in vivo after injection of amidated glucoseoxidase (aGO) showed only a moderate IGF-1 response. This lack of total recovery was not due to chondrocyte death or to retained aGO producing extra H2O2 during tissue culture. Further studies with isolated bovine chondrocytes revealed that H2O2 did not damage the IGF-1 receptor. Binding of radiolabelled IGF-1 to H2O2 treated chondrocytes was unimpaired. Our data indicate that H2O2 inhibits chondrocyte proteoglycan synthesis via a mechanism not related to disturbance of IGF-1 signalling. Transient chondrocyte IGF-1 nonresponsiveness found after H2O2 exposure is not related to IGF receptor damage, and contrasts with the complete nonresponsiveness found in arthritic cartilage.
Joosten
L A
LA
Department of Rheumatology, University of Nijmegen, The Netherlands.
Helsen
M M
MM
van den Berg
W B
WB
D000818:Animals; D001168:Arthritis / Q000473:pathology; D001345:Autoradiography; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D017451:Receptors, Somatomedin; D012016:Reference Values; D013002:Somatomedins / Q000378:metabolism
D016166:Free Radical Scavengers; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D010100:Oxygen