Specific inhibition of basic calcium phosphate and calcium pyrophosphate crystal-induction of metalloproteinase synthesis by phosphocitrate.
Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystal deposition diseases are a group of heterogeneous arthritides which are a significant source of morbidity in the elderly. Both crystals induced mitogenesis and metalloproteinase (MP) synthesis and secretion by fibroblasts and chondrocytes which may promote degradation of intra-articular tissue. We have previously shown that phosphocitrate (PC), an inhibitor of hydroxyapatite crystallization, specifically blocks BCP crystal-induced mitogenesis in 3T3 cells. This led us to examine the effect of PC on BCP and CPPD crystal induction of MP synthesis in human fibroblasts. PC (10(-3) to 10(-4) M) specifically inhibited the crystal-induced collagenase and stromelysin mRNA accumulation while having no effect on epidermal growth factor-induced or basal levels of mRNA for both enzymes. Western blots (collagenase) of conditioned media confirmed that PC blocked crystal-induced proteinase secretion as well. Moreover, PC (10(-3) M) also blocked the crystal induction of c-fos and c-jun. Since FOS and JUN proteins form a transacting activator (AP-1) for expression of collagenase and stromelysin genes, PC may block the synthesis of both enzymes by inhibiting the transcription of c-fos and c-jun.
Cheung
H S
HS
Division of Rheumatology, Medical College of Wisconsin, Milwaukee, 53226, USA.
Sallis
J D
JD
Struve
J A
JA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000368:Aged; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002114:Calcinosis / Q000378:metabolism; D002130:Calcium Phosphates / Q000494:pharmacology*; D002478:Cells, Cultured; D002951:Citrates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D003460:Crystallization; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D015342:DNA Probes; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts; D016758:Genes, jun; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009017:Morbidity; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012867:Skin / Q000201:enzymology*
D002130:Calcium Phosphates; D002951:Citrates; D015342:DNA Probes; D016755:Proto-Oncogene Proteins c-jun; C485828:alpha-tricalcium phosphate; C485830:tetracalcium phosphate; D005576:Colforsin; C014148:phosphocitrate; C485838:calcium phosphate, monobasic, anhydrous; D004247:DNA; C020243:calcium phosphate; D000242:Cyclic AMP; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; C485829:calcium phosphate, dibasic, anhydrous; D015056:1-Methyl-3-isobutylxanthine