The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated
The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated
复制标题
DOI：
10.1210/endo.141.12.7840
复制
发表时间：
2000-12-01
期刊：
影响因子：
4.8
通讯作者：
Riggs, BL
中科院分区：
文献类型：
--
作者：
Gori, F;Hofbauer, LC;Riggs, BL
在骨重塑过程中，一个或多个决定骨吸收和骨形成的分子机制尚不清楚。RANK配体（RANK- l）是破骨细胞形成的必要条件，其活性通过与可溶性诱饵受体骨保护素（OPG）结合而被中和。由于这两种分子都是由成骨细胞谱系细胞产生的，我们在条件永生化的人骨髓基质（hMS[2-15]）细胞系中研究了它们的发育调控。这些细胞可以模拟从未分化的前体细胞到能够形成矿化结节的完整成骨细胞表型的完整发育序列。在成骨细胞分化过程中，RANK-L信使RNA水平下降了5倍，而OPG信使RNA水平增加了7倍，导致RANK-L/OPG比值变化了35倍。OPG蛋白也增加了6倍。小鼠骨髓细胞与未分化的hMS（2-15）细胞共培养产生破骨细胞样细胞，但与处于不同分化阶段的hMS（2-15）细胞共培养时，除非添加过量的RANK-L，否则不能产生破骨细胞样细胞。因此，具有高RANK-L/OPG比率的未分化骨髓基质细胞可以启动和支持破骨细胞的发生，但在分化为成熟的成骨细胞表型后，它们不能。我们推测基质/成骨细胞对OPG和RANK-L产生的发育性调节有助于在骨重塑周期中破骨细胞和成骨细胞分化的协调序列。
The one or more molecular mechanisms that determine the obligatory sequence of resorption followed by formation during bone remodeling is unclear. RANK ligand (RANK-L) is an essential requirement for osteoclastogenesis, and its activity is neutralized by binding to the soluble decoy receptor, osteoprotegerin (OPG). Because both molecules are produced by osteoblast lineage cells, we studied their developmental regulation in a conditionally immortalized human marrow stromal (hMS[2-15]) cell line. These cells can simulate the complete developmental sequence from undifferentiated precursor(s) to cells with the complete osteoblast phenotype that are capable of forming mineralized nodules. During osteoblast differentiation, RANK-L messenger RNA levels decreased by 5-fold, whereas OPG messenger RNA levels increased by 7-fold, resulting in a 35-fold change in the RANK-L/OPG ratio. OPG protein also increased by 6-fold. Mouse hone marrow cells generated osteoclast-like cells in coculture with undifferentiated hMS(2-15) cells, but did not when cocultured with hMS(2-15) cells in varying stages of differentiation, unless an excess of RANK-L was added. Thus, undifferentiated marrow stromal cells with a high RANK-L/OPG ratio can initiate and support osteoclastogenesis, but after differentiation to the mature osteoblast phenotype, they cannot. We speculate that the develop mental regulation of OPG and RANK-L production by stromal/osteoblast cells contributes to the coordinated sequence of osteoclast and osteoblast differentiation during the hone remodeling cycle.