Zanotti Stefano, Smerdel-Ramoya Anna, Stadmeyer Lisa, Canalis Ernesto
Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105-1299, USA.
J Cell Biochem. 2008 Jul 1;104(4):1421-6. doi: 10.1002/jcb.21715.
Gremlin is a glycoprotein that binds and antagonizes the actions of bone morphogenetic proteins (BMPs) -2, -4, and -7. Gremlin appears to activate the extracellular regulated kinase (ERK) pathway in endothelial and tumor cells, and as a consequence to have direct cellular effects. To determine whether gremlin has direct effects in osteoblasts, independent of its BMP binding activity, we examined its effects in ST-2 murine stromal cell lines and in primary cultures of murine calvarial osteoblasts. Gremlin did not activate Signaling mothers against decapentaplegic (Smad), and suppressed the BMP-2 induced Smad 1/5/8 phosphorylation and the transactivation of the BMP/Smad reporter construct 12xSBE-Oc-pGL3, confirming its BMPs antagonizing activity. Neither gremlin nor BMP-2 induced ERK 1/2 activation in ST-2 cells or calvarial osteoblasts. Moreover, slight changes in culture conditions induced the phosphorylation of ERK independent from BMP or gremlin exposure. In conclusion, gremlin inhibits BMP-2 signaling and activity, and does not have independent actions on ERK signaling in osteoblasts. Consequently, gremlin activity in osteoblasts can be attributed only to its BMP antagonizing effects.
Gremlin是一种糖蛋白，它能结合并拮抗骨形态发生蛋白（BMP）-2、-4和-7的作用。Gremlin似乎能激活内皮细胞和肿瘤细胞中的细胞外调节激酶（ERK）通路，并因此产生直接的细胞效应。为了确定Gremlin在成骨细胞中是否具有直接作用，而不依赖于其BMP结合活性，我们检测了它对ST-2小鼠基质细胞系和小鼠颅骨成骨细胞原代培养物的影响。Gremlin未激活抗五聚体瘫信号转导蛋白（Smad），并抑制了BMP-2诱导的Smad 1/5/8磷酸化以及BMP/Smad报告基因构建体12xSBE-Oc-pGL3的反式激活，证实了其对BMP的拮抗活性。Gremlin和BMP-2均未在ST-2细胞或颅骨成骨细胞中诱导ERK 1/2激活。此外，培养条件的轻微变化会诱导ERK磷酸化，且与BMP或Gremlin暴露无关。总之，Gremlin抑制BMP-2信号传导和活性，且对成骨细胞中的ERK信号传导没有独立作用。因此，Gremlin在成骨细胞中的活性只能归因于其对BMP的拮抗作用。
