Commitment to the Osteoblast Lineage Is Not Required for RANKL Gene Expression
Commitment to the Osteoblast Lineage Is Not Required for RANKL Gene Expression
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DOI：
10.1074/jbc.m806628200
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发表时间：
2009-05-08
影响因子：
4.8
通讯作者：
O'Brien, Charles A.
中科院分区：
文献类型：
--
作者：
Galli, Carlo;Fu, Qiang;O'Brien, Charles A.
破骨细胞从造血祖细胞分化为骨吸收破骨细胞依赖于成纤维细胞基质细胞表达细胞因子受体激活剂核因子kappaB配体(RANKL)，有证据表明RANKL属于成骨细胞系。我们以前已经证明，小鼠RANKL基因的激素反应部分是由与Runx2结合的末端增强子介导的，Runx2是一种承诺成骨细胞谱系所需的转录因子，支持破骨细胞支持基质细胞可能是成骨细胞或其祖细胞的观点。然而，在这项研究中，我们证明甲状旁腺激素(PTH)对小鼠RANKL的刺激不受成骨细胞数量显著减少的影响。与此一致，在成纤维细胞基质细胞模型中，Runx2和RUNX活性所必需的结合伙伴Cbfb都不是基础的或PTH刺激的RANKL表达所必需的。然而，在高水平表达成骨细胞分化所需的另一种转录因子Osterix的培养的头盖骨细胞中，RANKL对PTH的反应性增加，这与PTH受体的表达增加有关。在表达Osterix的细胞中，RANKL对1，25-二羟基维生素D-3的反应性不升高。综上所述，这些结果表明，对成骨细胞系的承诺不是成纤维细胞基质细胞RANKL基因转录的必要条件，但可能通过控制其受体来增强该基因对特定激素的反应性。
Differentiation of bone-resorbing osteoclasts from hematopoietic precursors depends upon expression of the cytokine receptor activator of NF kappa B ligand (RANKL) by fibroblastic stromal cells, which some evidence suggests are of the osteoblast lineage. We have shown previously that hormonal-responsiveness of the murine RANKL gene is mediated in part by a distal enhancer that binds Runx2, a transcription factor required for commitment to the osteoblast lineage, supporting the idea that osteoclast-supporting stromal cells may be osteoblasts or their progenitors. However, in this study we demonstrate that parathyroid hormone (PTH) stimulation of RANKL in mice is not affected by a significant reduction in the number of osteoblasts. Consistent with this, neither Runx2, nor Cbfb, a binding partner essential for Runx activity, are required for basal or PTH-stimulated RANKL expression in fibroblastic stromal cell models. Nonetheless, RANKL responsiveness to PTH was elevated in cultured calvaria cells expressing high levels of osterix, another transcription factor required for osteoblast differentiation, and this was associated with elevated PTH receptor expression. The responsiveness of RANKL to 1,25-dihydroxyvitamin D-3 was not elevated in the osterix-expressing cells. Together, these results suggest that commitment to the osteoblast lineage is not a requirement for RANKL gene transcription in fibroblastic stromal cells but may enhance responsiveness of this gene to specific hormones via control of their receptors.