Bcl-2 regulates chondrocyte morphology and aggrecan gene expression independent of caspase activation and full apoptosis.
Bcl-2 is widely expressed in a variety of cell types and is known to block apoptosis through a conserved pathway. However, recent reports have demonstrated that Bcl-2 regulates cell behavior independent of its control of apoptosis. Chondrocytes express a unique set of matrix proteins, including the proteoglycan aggrecan, and have been widely used to study the relationship between trophic factors and apoptosis. In this article, we report that Bcl-2 affects the morphology and regulates the expression of aggrecan in a rat chondrocyte cell line (IRC). Endogenous Bcl-2 and aggrecan mRNA were both down-regulated in response to serum withdrawal in parental IRC cells, while constitutive expression of Bcl-2 maintained aggrecan levels under conditions of serum withdrawal. In addition, expression of anti-sense Bcl-2 resulted in decreased aggrecan mRNA and produced a fibroblastic morphology compared with parental cells. The caspase inhibitor ZVAD-fmk effectively blocked full apoptosis of IRC cells in response to serum withdrawal or anti-sense Bcl-2 but did not prevent the down-regulation of aggrecan expression from either signal. These results suggest a novel role for Bcl-2 in regulating the differentiated phenotype of chondrocytes and the expression of a differentiation-specific gene independent of its control of apoptosis.
Feng
L
L
Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Balakir
R
R
Precht
P
P
Horton
W E
WE
D053674:Aggrecans; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation / Q000235:genetics; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D037181:Lectins, C-Type; D011509:Proteoglycans / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
C508321:Acan protein, rat; D053674:Aggrecans; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans; D019253:Proto-Oncogene Proteins c-bcl-2; D016372:RNA, Antisense; D012333:RNA, Messenger; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases