Epidermal growth factor stimulates proton efflux from chondrocytic cells.
Proton efflux from chondrocytes alters the extracellular pH and ionic composition of cartilage, and influences the synthesis and degradation of extracellular matrix. Epidermal growth factor (EGF) promotes chondrocyte proliferation during skeletal development and accumulates in the synovial fluid in rheumatoid arthritis. The purpose of this study was to investigate the effect of EGF on proton efflux from chondrocytes. When monitored using a Cytosensor microphysiometer, EGF was found to rapidly activate proton efflux from CFK2 chondrocytic cells and rat articular chondrocytes. The actions of EGF were concentration-dependent with half-maximal effects at 0.3-0.7 ng/ml. Partial desensitization and time-dependent recovery of the response were observed following repeated exposures to EGF. EGF-induced proton efflux was dependent on extracellular glucose, and inhibitors of Na(+)/H(+) exchange (NHE) markedly attenuated the initial increase in proton efflux. The response was diminished by inhibitors of phosphatidylinositol 3-kinase and phospholipase C, but not by inhibitors of MEK (MAPK/ERK kinase) or protein kinase A or C. Thus, EGF-induced proton efflux involves glucose metabolism and NHE, and is regulated by a discrete subset of EGF-activated signaling pathways. In vivo, proton efflux induced by EGF may lead to an acidic environment, enhancing turnover of cartilage matrix during development and in rheumatoid arthritis.
CIHR Group in Skeletal Development and Remodeling, Department of Physiology, Faculty of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
Kevin E H
KE
Lui
Amiesha S
AS
Panchal
Anu
A
Santhanagopal
S Jeffrey
SJ
Dixon
Suzanne M
SM
Bernier
D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology; D005947:Glucose / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D010738:Type C Phospholipases / Q000502:physiology
D011522:Protons; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D010738:Type C Phospholipases; D005947:Glucose