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J. Biol. Chem., Vol. 277, Issue 17, 15190-15198, April 26, 2002
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From the Synovial fluid basic calcium phosphate (BCP)
crystals are common in osteoarthritis and are often associated with
destructive arthropathies involving cartilage degeneration. These
crystals are mitogenic and induce oncogene expression and matrix
metalloproteinase (MMP) synthesis and secretion in human fibroblasts.
To date, BCP crystal-elicited signal transduction pathways have not
been completely studied. Because protein kinase C (PKC) is known to
play an important role in signal transduction, we investigated the
participation of this pathway in the BCP crystal induction of MMP-1 and
MMP-3 mRNA and protein expressions in human fibroblasts. Using
reverse transcription/polymerase chain reaction (RT-PCR) and Northern and Western blotting techniques, we show here that BCP crystal stimulation of MMP-1 and MMP-3 mRNA and protein expressions in human fibroblasts is dependent upon the calcium-dependent
PKC signal transduction pathway and that the PKC
Molecular Mechanism of the Induction of Metalloproteinases 1 and 3 in Human Fibroblasts by Basic Calcium Phosphate Crystals
ROLE OF CALCIUM-DEPENDENT PROTEIN KINASE C
*
,¶
**
Department of Medicine, University of Miami
School of Medicine, Miami, Florida 33101, the § Department
of Human Genetics, University of Michigan Medical School, Ann Arbor,
Michigan, 48109-0618, the ¶ Research Service & Geriatric Research,
Education and Clinical Center, Veterans Administration Medical Center,
Miami, Florida 33125, and the Department of Biomedical
Engineering, University of Miami, Coral Gables, Florida 33146
isozyme is
specifically involved in the pathway. We have previously shown that BCP
crystal induction of MMP-1 and MMP-3 is also dependent on the p44/42
mitogen-activated protein kinase (p44/42 MAPK) signal transduction
pathway. We now show that these two pathways operate independently and
seem to complement each other. This leads to our hypothesis that the
two pathways initially function independently, ultimately leading to an
increase in mitogenesis and MMP synthesis, and may converge downstream
of PKC and p44/42 MAPK to mediate BCP crystal-induced cellular responses.
*
This work was supported by United States Public Health
Services Grant AR-38421-13 and by a Veteran Administration Merit Review grant (to H. S. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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