Teplyuk Nadiya M, Haupt Larisa M, Ling Ling, Dombrowski Christian, Mun Foong Kin, Nathan Saminathan S, Lian Jane B, Stein Janet L, Stein Gary S, Cool Simon M, van Wijnen Andre J
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0105, USA.
J Cell Biochem. 2009 May 1;107(1):144-54. doi: 10.1002/jcb.22108.
Heparan sulfate proteoglycans cooperate with basic fibroblast growth factor (bFGF/FGF2) signaling to control osteoblast growth and differentiation, as well as metabolic functions of osteoblasts. FGF2 signaling modulates the expression and activity of Runt-related transcription factor 2 (Runx2/Cbfa1), a key regulator of osteoblast proliferation and maturation. Here, we have characterized novel Runx2 target genes in osteoprogenitors under conditions that promote growth arrest while not yet permitting sustained phenotypic maturation. Runx2 enhances expression of genes related to proteoglycan-mediated signaling, including FGF receptors (e.g., FGFR2 and FGFR3) and proteoglycans (e.g., syndecans [Sdc1, Sdc2, Sdc3], glypicans [Gpc1], versican [Vcan]). Runx2 increases expression of the glycosyltransferase Exostosin-1 (Ext1) and heparanase, as well as alters the relative expression of N-linked sulfotransferases (Ndst1 = Ndst2 > Ndst3) and enzymes mediating O-linked sulfation of heparan sulfate (Hs2st > Hs6st) or chondroitin sulfate (Cs4st > Cs6st). Runx2 cooperates with FGF2 to induce expression of Sdc4 and the sulfatase Galns, but Runx2 and FGF2 suppress Gpc6, thus suggesting intricate Runx2 and FGF2 dependent changes in proteoglycan utilization. One functional consequence of Runx2 mediated modulations in proteoglycan-related gene expression is a change in the responsiveness of bone markers to FGF2 stimulation. Runx2 and FGF2 synergistically enhance osteopontin expression (>100 fold), while FGF2 blocks Runx2 induction of alkaline phosphatase. Our data suggest that Runx2 and the FGF/proteoglycan axis may form an extracellular matrix (ECM)-related regulatory feed-back loop that controls osteoblast proliferation and execution of the osteogenic program.
硫酸乙酰肝素蛋白聚糖与碱性成纤维细胞生长因子（bFGF/FGF2）信号通路协同作用，以控制成骨细胞的生长和分化以及成骨细胞的代谢功能。FGF2信号通路调节成骨细胞增殖和成熟的关键调节因子——Runx2/Cbfa1（Runt相关转录因子2）的表达和活性。在此，我们在促进生长停滞但尚未允许持续表型成熟的条件下，对骨祖细胞中的新型Runx2靶基因进行了表征。Runx2增强了与蛋白聚糖介导的信号传导相关的基因表达，包括FGF受体（如FGFR2和FGFR3）和蛋白聚糖（如多功能蛋白聚糖[Sdc1、Sdc2、Sdc3]、磷脂酰肌醇蛋白聚糖[Gpc1]、多功能蛋白聚糖[Vcan]）。Runx2增加了糖基转移酶外切糖苷酶-1（Ext1）和乙酰肝素酶的表达，同时改变了N-连接磺基转移酶（Ndst1 = Ndst2 > Ndst3）以及介导硫酸乙酰肝素O-连接硫酸化（Hs2st > Hs6st）或硫酸软骨素（Cs4st > Cs6st）的酶的相对表达。Runx2与FGF2协同诱导Sdc4和硫酸酯酶Galns的表达，但Runx2和FGF2抑制Gpc6，因此表明Runx2和FGF2在蛋白聚糖利用方面存在复杂的依赖性变化。Runx2介导的蛋白聚糖相关基因表达调节的一个功能后果是骨标志物对FGF2刺激的反应性发生变化。Runx2和FGF2协同增强骨桥蛋白的表达（>100倍），而FGF2阻断Runx2诱导的碱性磷酸酶。我们的数据表明，Runx2和FGF/蛋白聚糖轴可能形成一个与细胞外基质（ECM）相关的调节反馈环，控制成骨细胞的增殖和成骨程序的执行。
