Interleukin-1beta increases gap junctional communication among synovial fibroblasts via the extracellular-signal-regulated kinase pathway.
BACKGROUND
The gap junction protein, Cx43 (connexin 43), has been implicated in the aetiology of osteoarthritis. Studies have revealed that the size and number of gap junctions increase in synovial biopsies from patients with osteoarthritis. Furthermore, pharmacological inhibition of Cx43 function has been shown to reduce IL-1beta (interleukin-1beta)-induced metalloproteinase production by synovial fibroblasts in vitro.


RESULTS
In the present study, we examined the link between IL-1beta and Cx43 function. We demonstrated that treatment of a rabbit synovial fibroblast cell line with IL-1beta markedly increased the level of the Cx43 protein in a concentration- and time-dependent manner. The impact on Cx43 protein levels appeared to occur post-transcriptionally, as mRNA levels are unaffected by IL-1beta administration. Additionally, we showed by fluorescence microscopy that IL-1beta alters the cellular distribution of Cx43 to cell-cell junctions and is concomitant with a striking increase in gap junction communication. Furthermore, we demonstrated that the increase in Cx43 protein, and the associated change in protein localization and gap junction communication following IL-1beta treatment, are dependent upon activation of the ERK (extracellular-signal-regulated kinase) signalling cascade.


CONCLUSIONS
These data show that IL-1beta acts through the ERK signalling cascade to alter the expression and function of Cx43 in synovial fibroblasts.
Niger
Corinne
C
Department of Orthopaedics, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
Howell
Floyd D
FD
Stains
Joseph P
JP
D000818:Animals; D015153:Blotting, Western; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology*; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D018031:Connexin 43; D053583:Interleukin-1beta; D048049:Extracellular Signal-Regulated MAP Kinases