Bischoff D S, Zhu J H, Makhijani N S, Kumar A, Yamaguchi D T
Research Service, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA.
J Cell Biochem. 2008 Feb 15;103(3):812-24. doi: 10.1002/jcb.21450.
The potential role of ELR(+) CXC chemokines in early events in bone repair was studied using human mesenchymal stem cells (hMSCs). Inflammation, which occurs in the initial phase of tissue healing in general, is critical to bone repair. Release of cytokines from infiltrating immune cells and injured bone can lead to recruitment of MSCs to the region of repair. CXC chemokines bearing the Glu-Leu-Arg (ELR) motif are also released by inflammatory cells and serve as angiogenic factors stimulating chemotaxis and proliferation of endothelial cells. hMSCs, induced to differentiate with osteogenic medium (OGM) containing ascorbate, beta-glycerophosphate (beta-GP), and dexamethasone (DEX), showed an increase in mRNA and protein secretion of the ELR(+) CXC chemokines CXCL8 and CXCL1. CXCL8 mRNA half-life studies reveal an increase in mRNA stability upon OGM stimulation. Increased expression and secretion is a result of DEX in OGM and is dose-dependent. Inhibition of the glucocorticoid receptor with mifepristone only partially inhibits DEX-stimulated CXCL8 expression indicating both glucocorticoid receptor dependent and independent pathways. Treatment with signal transduction inhibitors demonstrate that this expression is due to activation of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways and is mediated through the G(alphai)-coupled receptors. Angiogenesis assays demonstrate that OGM-stimulated conditioned media containing secreted CXCL8 and CXCL1 can induce angiogenesis of human microvascular endothelial cells in an in vitro Matrigel assay.
利用人间充质干细胞（hMSCs）研究了ELR(+) CXC趋化因子在骨修复早期事件中的潜在作用。炎症通常发生在组织愈合的初始阶段，对骨修复至关重要。浸润的免疫细胞和受损骨释放的细胞因子可导致间充质干细胞募集到修复区域。带有Glu-Leu-Arg（ELR）基序的CXC趋化因子也由炎症细胞释放，并作为血管生成因子刺激内皮细胞的趋化性和增殖。用含有抗坏血酸、β-甘油磷酸酯（β-GP）和地塞米松（DEX）的成骨培养基（OGM）诱导hMSCs分化后，ELR(+) CXC趋化因子CXCL8和CXCL1的mRNA和蛋白分泌增加。CXCL8 mRNA半衰期研究表明，OGM刺激后mRNA稳定性增加。表达和分泌的增加是OGM中DEX的作用结果，且呈剂量依赖性。用米非司酮抑制糖皮质激素受体仅部分抑制DEX刺激的CXCL8表达，表明存在糖皮质激素受体依赖性和非依赖性途径。信号转导抑制剂处理表明，这种表达是由于ERK和p38丝裂原活化蛋白激酶（MAPK）途径的激活，并通过G(alphai)偶联受体介导。血管生成试验表明，含有分泌的CXCL8和CXCL1的OGM刺激的条件培养基可在体外基质胶试验中诱导人微血管内皮细胞的血管生成。
