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J Biol Chem, Vol. 273, Issue 52, 35161-35169, December 25, 1998

Molecular Mechanism of Basic Calcium Phosphate Crystal-induced Activation of Human Fibroblasts
ROLE OF NUCLEAR FACTOR B, ACTIVATOR PROTEIN 1, AND PROTEIN KINASE C

Geraldine M. McCarthy, James A. Augustine^§, Albert S. Baldwin^¶, Pamela A. Christopherson, Herman S. Cheung, Pamela R. Westfall, and Robert I. Scheinman^**

From the ^§ Department of Medicine (Rheumatology), Medical College of Wisconsin and the Blood Research Institute, Milwaukee, Wisconsin 53226, the ^¶ Lineberger Comprehensive Cancer Institute, University of North Carolina, Chapel Hill, North Carolina 27599, the  Department of Medicine (Arthritis), University of Miami School of Medicine and Geriatric Research, Education and Clinical Center, Veterans Administration Medical Center, Miami, Florida 33125, and the ^** School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262

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 B 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.

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