Dexamethasone promotes calcium pyrophosphate dihydrate crystal formation by articular chondrocytes.
OBJECTIVE
Calcium pyrophosphate dihydrate (CPPD) crystals are commonly found in osteoarthritic joints and correlate with a poor prognosis. Intraarticular corticosteroids, such as dexamethasone (Dxm), are commonly used therapies for osteoarthritis with or without CPPD deposition. Dxm has variable effects in mineralization models. We investigated the effects of Dxm on CPPD crystal formation in a well established tissue culture model.


METHODS
Porcine articular chondrocytes were incubated with ATP to generate CPPD crystals. Chondrocytes incubated with or without ATP were exposed to 1-100 nM Dxm in the presence of 45Ca. Mineralization was measured by 45Ca uptake in the cell layer. We also investigated the effect of Dxm on mineralization-regulating enzymes such as alkaline phosphatase, nucleoside triphosphate pyrophosphohydrolase (NTPPPH), and transglutaminase.


RESULTS
Dxm significantly increased ATP-induced mineralization by articular chondrocytes. While alkaline phosphatase and NTPPPH activities were unchanged by Dxm, transglutaminase activity increased in a dose-responsive manner. Levels of Factor XIIIA mRNA and protein were increased by Dxm, while type II Tgase protein was unchanged. Transglutaminase inhibitors suppressed Dxminduced increases in CPPD crystal formation.


CONCLUSIONS
These findings suggest a potential for Dxm to contribute to pathologic mineralization in cartilage and reinforce a central role for the transglutaminase enzymes in CPPD crystal formation.
Fahey
Mark
M
Department of Medicine, Medical College of Wisconsin, Rheumatology Section, cc-111W, Zablocki VA Medical Center, 5000 W. National Ave., Milwaukee, WI 53295-1000, USA.
Mitton
Elizabeth
E
Muth
Emily
E
Rosenthal
Ann K
AK
D000818:Animals; D002131:Calcium Pyrophosphate / Q000737:chemistry*; D002132:Calcium Radioisotopes; D002358:Cartilage, Articular / Q000166:cytology; D002478:Cells, Cultured; D002805:Chondrocalcinosis / Q000139:chemically induced* / Q000473:pathology; D019902:Chondrocytes / Q000737:chemistry* / Q000187:drug effects* / Q000201:enzymology; D003460:Crystallization; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D013552:Swine; D013722:Teprotide / Q000494:pharmacology; D011503:Transglutaminases / Q000037:antagonists & inhibitors
D002132:Calcium Radioisotopes; D005938:Glucocorticoids; D003907:Dexamethasone; D013722:Teprotide; D011503:Transglutaminases; D002131:Calcium Pyrophosphate