Molecular mechanism of basic calcium phosphate crystal-induced activation of human fibroblasts. Role of nuclear factor kappab, activator protein 1, and protein kinase c.
Synovial fluid basic calcium phosphate (BCP) crystals are markers of severe joint degeneration in osteoarthritis. BCP crystals cause mitogenesis of articular cells and stimulate matrix metalloprotease production, thus promoting degradation of articular tissues. Previous work suggested that BCP crystal-induced cell activation required intracellular crystal dissolution, induction of proto-oncogene expression, and activation of signal transduction pathways involving protein kinase C and mitogen-activated protein kinases. Here we further elucidate the mechanisms of BCP crystal-induced cell activation as BCP crystals activate transcription factors nuclear factor kappaB and activator protein 1 in human fibroblasts. We confirm the role of protein kinase C in BCP crystal-induced mitogenesis in human fibroblasts. In contrast, we demonstrate that BCP crystals do not activate signal transduction pathways involving protein tyrosine kinases or phosphatidylinositol 3-kinase. These data further define the mechanism of cell activation by BCP crystals and confirm its selectivity, an observation that may have therapeutic implications.
McCarthy
G M
GM
Department of Medicine (Rheumatology), Medical College of Wisconsin and the Blood Research Institute, Milwaukee, Wisconsin 53226, USA.
Augustine
J A
JA
Baldwin
A S
AS
Christopherson
P A
PA
Cheung
H S
HS
Westfall
P R
PR
Scheinman
R I
RI
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport; D002130:Calcium Phosphates / Q000494:pharmacology*; D017886:Durapatite / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007592:Joint Diseases / Q000209:etiology; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D002130:Calcium Phosphates; D017886:Durapatite; D008934:Mitogens; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C000715470:MAS1 protein, human; C485828:alpha-tricalcium phosphate; C485830:tetracalcium phosphate; C022045:octacalcium phosphate; C485838:calcium phosphate, monobasic, anhydrous; C020243:calcium phosphate; C485829:calcium phosphate, dibasic, anhydrous