Ling Ling, Murali Sadasivam, Dombrowski Christian, Haupt Larisa M, Stein Gary S, van Wijnen Andre J, Nurcombe Victor, Cool Simon M
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673.
J Cell Physiol. 2006 Dec;209(3):811-25. doi: 10.1002/jcp.20760.
Fibroblast growth factor-2 (FGF2) is a powerful promoter of bone growth. We demonstrate here that brief exposure to FGF2 enhances mineralized nodule formation in cultured rat osteoprogenitor cells due to an expansion of cells that subsequently mineralize. This mitogenic effect is mediated via sulfated glycosaminoglycans (GAGs), FGFR1, and the extracellular signal-regulated kinase (ERK) pathway. The GAGs involved in this stimulation are chondroitin sulfates (CS) rather than heparan sulfates (HS). However, continuous FGF2 treatment reduces alkaline phosphatase (ALP) activity, downregulates collagen Ialpha1 (ColIalpha1) and FGFR3 expression, upregulates the expression and secretion of osteopontin (OPN) and inhibits mineralization. The inhibitory effects of FGF2 on FGFR3 expression and ALP activity are also mediated by the ERK pathway, although the effects of FGF2 on ColIalpha1 and OPN expression are mediated by GAGs and PKC activity. Thus short-term activation of FGF2/FGFR1 promotes osteoprogenitor proliferation and subsequent differentiation, while long-term activation of FGF2 signaling disrupts mineralization by modulating osteogenic marker expression. This study thus establishes the central role of sulfated GAGs in the osteogenic progression of osteoprogenitors.
成纤维细胞生长因子-2（FGF2）是骨生长的有力促进因子。我们在此证明，短暂暴露于FGF2可增强培养的大鼠骨祖细胞中矿化结节的形成，这是由于随后矿化的细胞数量增加所致。这种促有丝分裂作用是通过硫酸化糖胺聚糖（GAGs）、FGFR1和细胞外信号调节激酶（ERK）途径介导的。参与这种刺激的GAGs是硫酸软骨素（CS）而非硫酸乙酰肝素（HS）。然而，持续的FGF2处理会降低碱性磷酸酶（ALP）活性，下调I型胶原蛋白α1（ColIα1）和FGFR3的表达，上调骨桥蛋白（OPN）的表达和分泌并抑制矿化。FGF2对FGFR3表达和ALP活性的抑制作用也由ERK途径介导，尽管FGF2对ColIα1和OPN表达的影响是由GAGs和PKC活性介导的。因此，FGF2/FGFR1的短期激活促进骨祖细胞增殖及随后的分化，而FGF2信号的长期激活则通过调节成骨标志物表达来破坏矿化。本研究因此确立了硫酸化GAGs在骨祖细胞成骨进程中的核心作用。
