Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism.
Diseases caused by calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals occur frequently in osteoarthritic joints. Both crystals induce mitogenesis, metalloproteinase synthesis and secretion by fibroblasts and chondrocytes, promoting degradation of articular tissue. We investigated the mechanism by which BCP activates the c-fos proto-oncogene, which has been shown to activate various matrix metalloproteinases (MMPs). We demonstrate that BCP crystals induce c-fos expression primarily through a Ras/ERK-dependent signaling mechanism targeting two highly conserved regulatory binding sites, the serum response element (SRE) and the cAMP response element (CRE). These results establish a calcium crystal induced, calcium/calmodulin independent, signaling pathway in which BCP crystals activate Ras/MAPK, which can directly target an SRF-containing transcription factor complex, to induce fibroblasts to secrete metalloproteinases.
Major
Michael L
ML
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cheung
Herman S
HS
Misra
Ravi P
RP
D000818:Animals; D002130:Calcium Phosphates / Q000737:chemistry / Q000633:toxicity*; D002478:Cells, Cultured; D003460:Crystallization; D000242:Cyclic AMP / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010003:Osteoarthritis / Q000139:chemically induced; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects; D027602:Serum Response Element / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D002130:Calcium Phosphates; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; C020243:calcium phosphate; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D015689:Oncogene Protein p21(ras)