p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF-beta.
These studies compare actions of p38 MAPK inhibition and COX2 inhibition to modulate human arthritic chondrocyte responses to TGF-beta and FCS under basal and IL-1 activated conditions. Chondrocytes isolated from arthritic human femoral condyle cartilage obtained at total knee replacement were grown to 80% confluence. Proteoglycan synthesis and proliferation were measured with and without IL-1 activation in the presence and absence of growth factors and with and without inhibition of p38 MAPK or COX2 activity. Experiments to evaluate TIMP-1 production under these conditions were done using cartilage organ cultures. Neither p38 MAPK inhibitors nor COX2 inhibition affected basal proliferation. However both inhibitors enhanced the proliferative response to TGF-beta and FCS in IL-1 activated chondrocytes. TGF-beta stimulated proteoglycan synthesis was decreased by p38 MAPK inhibition, however COX2 inhibition restored the response to TGF-beta in IL-1 activated cells. In contrast, COX2 inhibition did not modulate TIMP-1 production while p38 MAPK inhibitors potentiated TGF-beta stimulated production of TIMP-1 in IL-1 activated cartilage. p38 MAPK inhibition and COX2 inhibition have unique and similar abilities to counteract some of the effects of IL-1 on human chondrocyte/cartilage metabolism. Both will partially restore the proliferative response to growth factors. p38 MAPK inhibition blunts TGF-beta stimulation of proteoglycan synthesis, but increases TIMP-1 synthesis. COX2 inhibition can restore the proteoglycan synthetic response to TGF-beta, but has no effect on cartilage TIMP-1 production. Use of these inhibitors to minimize cartilage damage in arthritic and mechanically stressed joints should reflect these characteristics.
Studer
Rebecca K
RK
VA Pittsburgh Healthcare System, University of Pittsburgh Medical School, Pittsburgh, PA 15240, USA. rstuder@pitt.edu
Chu
Constance R
CR
D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D011509:Proteoglycans / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D011509:Proteoglycans; D011725:Pyridines; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580