Evidence of a direct role for Bcl-2 in the regulation of articular chondrocyte apoptosis under the conditions of serum withdrawal and retinoic acid treatment.
The regulation of chondrocyte apoptosis in articular cartilage may underlay age-associated changes in cartilage and the development of osteoarthritis. Here we demonstrate the importance of Bcl-2 in regulating articular chondrocyte apoptosis in response to both serum withdrawal and retinoic acid treatment. Both stimuli induced apoptosis of primary human articular chondrocytes and a rat chondrocyte cell line as evidenced by the formation of DNA ladders. Apoptosis was accompanied by decreased expression of aggrecan, a chondrocyte specific matrix protein. The expression of Bcl-2 was downregulated by both agents based on Northern and Western analysis, while the level of Bax expression remained unchanged compared to control cells. The importance of Bcl-2 in regulating chondrocyte apoptosis was confirmed by creating cell lines overexpressing sense and antisense Bcl-2 mRNA. Multiple cell lines expressing antisense Bcl-2 displayed increased apoptosis even in the presence of 10% serum as compared to wild-type cells. In contrast, chondrocytes overexpressing Bcl-2 were resistant to apoptosis induced by both serum withdrawal and retinoic acid treatment. Finally, the expression of Bcl-2 did not block the decreased aggrecan expression in IRC cells treated with retinoic acid. We conclude that Bcl-2 plays an important role in the maintenance of articular chondrocyte survival and that retinoic acid inhibits aggrecan expression independent of the apoptotic process.
Feng
L
L
Laboratory of Biological Chemistry, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
Precht
P
P
Balakir
R
R
Horton
W E
WE
D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001769:Blood; D002358:Cartilage, Articular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology*
D019253:Proto-Oncogene Proteins c-bcl-2; D014212:Tretinoin