Signal transduction in electrically stimulated articular chondrocytes involves translocation of extracellular calcium through voltage-gated channels

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Signal transduction in electrically stimulated articular chondrocytes involves translocation of extracellular calcium through voltage-gated channels J. Xu, M.D., Ph.D., W. Wang, M.D., C.C. Clark, Ph.D., C.T. Brighton, M.D., Ph.D. Osteoarthritis and Cartilage Volume 17, Issue 3, Pages 397-405 (March 2009) DOI: 10.1016/j.joca.2008.07.001 Copyright © 2008 Terms and Conditions

Fig. 1 Experimental design showing the protocol followed for all experiments. All cultures were grown for 7 days and were treated on the 8th day. For aggrecan and collagen experiments, cells were incubated in the absence or presence of signal transduction pathway inhibitors for 2h prior to initiation of electrical stimulation at 60kHz and 20mV/cm (1h at 50% duty cycle for aggrecan, gray box, and 6h at 8.3% duty cycle for type II collagen, white box); samples were harvested 4h and 6h after initiation of electrical stimulation, respectively. For metalloproteinase experiments, cells were incubated in the absence or presence of signal transduction pathway inhibitors and/or IL-1β for 2h prior to initiation of electrical stimulation (30min at 100% duty cycle, black box); samples were harvested 22h after initiation of electrical stimulation. Osteoarthritis and Cartilage 2009 17, 397-405DOI: (10.1016/j.joca.2008.07.001) Copyright © 2008 Terms and Conditions

Fig. 2 Schematic diagram of relevant calcium signal transduction pathways showing the steps inhibited (indicated by a red ×) by the specific compounds tested. The main pathway of interest involves the opening of voltage-gated calcium channels (blocked by verapamil) by electrical stimulation, allowing the entry of extracellular Ca2+ resulting in elevated cytoplasmic Ca2+ levels. This results in activation of calmodulin (blocked by W-7) and the subsequent activation of calcineurin which dephosphorylates NF-AT (blocked by cyclosporin A). NF-AT then translocates to the nucleus where it acts in conjunction with other associated proteins as transcription factors. Another calcium-related pathway involves the conversion of PIP2 to IP3 by the action of phospholipase C (blocked by neomycin) and the IP3-induced release of intracellular Ca2+ stores to the cytoplasm (blocked by cyclosporin A and TMB-8). An increase in intracellular Ca2+ can also increase in PLA2 activity (blocked by BPB) leading to PGE2 synthesis (blocked by indomethacin). IP3R=inositol 1,4,5-triphosphate receptor, TF=any one or more generic transcription factors associated with NF-AT (Diagram adapted from Ref. 15). Osteoarthritis and Cartilage 2009 17, 397-405DOI: (10.1016/j.joca.2008.07.001) Copyright © 2008 Terms and Conditions

Fig. 3 Effect of signal transduction inhibitors on the regulation of aggrecan and type II collagen mRNA levels by electrical stimulation. For the groups labeled None, Neomycin, Verapamil and Cyclosporin, n=12; for all other groups, n=6. (A) Aggrecan expression. ∗ denotes P<0.0001, NS=not significant (P>0.99); ∗∗ denotes unstimulated groups not significantly different from each other (P>0.69); † denotes stimulated groups not significantly different from each other (P=0.24). (B) Type II collagen expression. ∗ denotes P<0.0001, NS=not significant (P=1); ∗∗ denotes unstimulated groups not significantly different from each other (P>0.99); † denotes stimulated groups not significantly different from each other (P>0.10). Osteoarthritis and Cartilage 2009 17, 397-405DOI: (10.1016/j.joca.2008.07.001) Copyright © 2008 Terms and Conditions

Fig. 4 Effect of IL-1β and/or signal transduction inhibitors on the regulation of MMP mRNA levels by electrical stimulation. For the groups labeled None, Neomycin, Verapamil and Cyclosporin, n=12; for all other groups, n=6. (A) MMP-1 expression. ∗ denotes P<0.0001, NS=not significant (P>0.99); ∗∗ denotes unstimulated groups not significantly different from each other (P>0.22); † denotes stimulated groups not significantly different from each other (P>0.55). (B) MMP-3 expression. ∗ denotes P<0.0001, NS=not significant (P>0.99); ∗∗ denotes unstimulated groups not significantly different from each other (P>0.47); † denotes stimulated groups not significantly different from each other (P>0.12). (C) MMP-13 expression. ∗ denotes P<0.0001, NS=not significant (P>0.99); ∗∗ denotes unstimulated groups not significantly different from each other (P>0.07); † denotes stimulated groups not significantly different from each other (P>0.89). Osteoarthritis and Cartilage 2009 17, 397-405DOI: (10.1016/j.joca.2008.07.001) Copyright © 2008 Terms and Conditions

Fig. 5 Effect of IL-1β and/or signal transduction inhibitors on the regulation of ADAMTS mRNA levels by electrical stimulation. For the groups labeled None, Neomycin, Verapamil and Cyclosporin, n=12; for all other groups, n=6. (A) ADAMTS-4 expression. ∗ denotes P<0.0001, NS=not significant (P>0.98); ∗∗ denotes unstimulated groups not significantly different from each other (P>0.94); † denotes stimulated groups not significantly different from each other (P>0.69). (B) ADAMTS-5 expression. ∗ denotes P<0.0001, NS=not significant (P>0.91); ∗∗ denotes unstimulated groups not significantly different from each other (P>0.95); † denotes stimulated groups not significantly different from each other (P=0.82). Osteoarthritis and Cartilage 2009 17, 397-405DOI: (10.1016/j.joca.2008.07.001) Copyright © 2008 Terms and Conditions