Paclitaxel selectively induces mitotic arrest and apoptosis in proliferating bovine synoviocytes.
OBJECTIVE
Rheumatoid arthritis (RA) is characterized by chronic progressive destruction of joints involving several disease processes, such as villous hypertrophy, proliferation of synovial lining cells, and infiltration of inflammatory cells. Synovial cell activation and proliferation is thought to be a key step in the destruction of cartilaginous and bony tissues in RA joints. In view of the invasive properties of synoviocytes in RA, we conducted in vitro studies to determine the mechanism of action of paclitaxel (Taxol) on synoviocytes, which may account for the inhibition of joint destruction found when this agent is administered.


METHODS
Cultured synovial cells were treated with various concentrations of paclitaxel and were evaluated by cell viability, fluorescence microscopy, flow cytometry of DAPI-stained cells, and electron microscopy.


RESULTS
The data indicated that paclitaxel inhibited synoviocyte proliferation by a G2/M phase block and was toxic to synoviocytes by inducing apoptosis. Confluent cells such as chondroyctes and synoviocytes were not affected by paclitaxel. Synchronization of synovioyctes at the G1/S boundary effectively abolished paclitaxel-induced apoptosis.


CONCLUSIONS
The data indicate that induction of apoptosis in synoviocytes might be dependent on transit through the cell cycle, specifically through G2 and mitosis. Further, paclitaxel was selectively toxic to proliferating synoviocytes but spared nonproliferating synoviocytes and chondrocytes. These results demonstrate that paclitaxel can inhibit synovial cell proliferation and pannus formation in RA joints in vivo. We suggest that paclitaxel be considered as a prototypical compound for a new class of potential chondroprotective agents.
Hui
A
A
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Kulkarni
G V
GV
Hunter
W L
WL
McCulloch
C A
CA
Cruz
T F
TF
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007399:Interphase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology*
D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel