Major Michael L, Cheung Herman S, Misra Ravi P
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Biochem Biophys Res Commun. 2007 Apr 13;355(3):654-60. doi: 10.1016/j.bbrc.2007.01.177. Epub 2007 Feb 7.
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.
由二水焦磷酸钙（CPPD）和碱性磷酸钙（BCP）晶体引起的疾病在骨关节炎关节中频繁发生。这两种晶体均可诱导成纤维细胞和软骨细胞发生有丝分裂、合成并分泌金属蛋白酶，从而促进关节组织的降解。我们研究了BCP激活原癌基因c-fos的机制，该基因已被证明可激活多种基质金属蛋白酶（MMPs）。我们证明，BCP晶体主要通过一种Ras/ERK依赖性信号传导机制诱导c-fos表达，该机制靶向两个高度保守的调节结合位点，即血清反应元件（SRE）和cAMP反应元件（CRE）。这些结果建立了一种钙晶体诱导的、钙/钙调蛋白独立的信号通路，其中BCP晶体激活Ras/MAPK，后者可直接靶向含SRF的转录因子复合物，诱导成纤维细胞分泌金属蛋白酶。
