<%@ Language=JavaScript %> Facilitation of fas mediated apoptosis of human chondrocytes by the proteasome inhibitor and actinomycin d

Facilitation of fas mediated apoptosis of human chondrocytes by the proteasome inhibitor and actinomycin d.

J Rheumatol 2003 Mar;30(3):550-8  

Kim HA, Kim YH, Song YW.

Department of Internal Medicine, Hallym University College of Medicine, Seoul, Korea.

OBJECTIVE: We investigated the susceptibility of chondrocytes to apoptosis induced by anti-Fas and various potentiators, and the relevant signaling pathway. METHODS: Chondrocytes were cultured from cartilages obtained at the time of joint replacement surgery for knee osteoarthritis (OA) or femur neck fracture. Fas receptor ligation was performed with agonistic anti-Fas antibody (clone CH-11) at concentrations ranging from 0.5 to 1.0 micro g/ml. Mitogen activated protein kinase inhibitors SB203580 and PD98059, cycloheximide, bisindolylmaleimide, actinomycin D, or MG132 were added with anti-Fas to facilitate cell death. Chondrocyte surface expression of Fas was analyzed by FACS, and the expression of apoptosis related proteins analyzed by Western blot. RESULTS: Cell death increased upon coculture with 0.5 micro g/ml of anti-Fas and 0.2 micro g/ml of actinomycin D or 20 micro M MG132. Apoptosis potentiated by actinomycin D or MG132 was effectively inhibited by caspase inhibitors, implicating the involvement of the caspase cascade in chondrocyte apoptosis. Compared with untreated cells or actinomycin D treated cells, cells treated with MG132 showed distinct shifts in the distribution of surface Fas fluorescence. Although concentrations of Bcl-2, Bax, FLICE inhibitory protein (FLIP), and Fas ligand were unaffected by MG132 or actinomycin D, both treatments led to a significant increase of p53. The expression of the p53 response proteins, MDM2 and p21, was elevated in MG132 treated chondrocytes. CONCLUSION: Our results suggest that chondrocytes can be rendered sensitive to anti-Fas mediated apoptosis by the proteasome inhibitor MG132 and the transcription inhibitor actinomycin D. MG132 and actinomycin D show different characteristics in terms of apoptosis signaling.

PMID: 12610816

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