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Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism
Michael L Major1, Herman S Cheung, Ravi P Misra
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Biochemical and Biophysical Research Communications
|February 20, 2007
Summary
Basic calcium phosphate (BCP) crystals activate the c-fos gene in osteoarthritic joints via a Ras/ERK pathway. This mechanism promotes the secretion of matrix metalloproteinases, contributing to joint tissue degradation.
Area of Science:
- Biochemistry
- Cell Biology
- Rheumatology
Background:
- Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals are implicated in osteoarthritic joint diseases.
- These crystals stimulate fibroblasts and chondrocytes, leading to articular tissue degradation via metalloproteinase synthesis and secretion.
Purpose of the Study:
- To elucidate the mechanism by which BCP crystals activate the c-fos proto-oncogene.
- To understand how BCP-induced c-fos activation contributes to matrix metalloproteinase (MMP) expression and subsequent joint tissue damage.
Main Methods:
- Investigated BCP crystal activation of c-fos proto-oncogene expression.
- Utilized cell culture models of fibroblasts and chondrocytes.
- Analyzed signaling pathways including Ras/ERK and their targets (SRE, CRE).
Main Results:
- BCP crystals induce c-fos expression predominantly through a Ras/ERK-dependent signaling pathway.
- This pathway targets conserved regulatory elements: the serum response element (SRE) and the cAMP response element (CRE).
- BCP-induced signaling is independent of calcium/calmodulin.
Conclusions:
- BCP crystals activate a novel signaling pathway involving Ras/MAPK.
- This pathway directly targets an SRF-containing transcription factor complex.
- BCP crystals induce fibroblasts to secrete matrix metalloproteinases, contributing to osteoarthritic joint degradation.
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