Conditional ablation of Pten in osteoprogenitors stimulates FGF signaling
Conditional ablation of Pten in osteoprogenitors stimulates FGF signaling
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DOI：
10.1242/dev.058016
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发表时间：
2011-04-01
期刊：
影响因子：
4.6
通讯作者：
Naski, Michael C.
中科院分区：
文献类型：
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作者：
Guntur, Anyonya R.;Reinhold, Martina I.;Naski, Michael C.
10号染色体上缺失的磷酸酶和张力蛋白同源基因(PTEN)是磷脂酰肌醇3激酶的直接拮抗剂。PTEN是公认的肿瘤抑制基因，也是人类恶性肿瘤中最常见的突变基因之一。最近对发育和干细胞行为的研究表明，PTEN调节祖细胞的生长和分化。值得注意的是，PTEN在成骨细胞的骨祖细胞中被发现；然而，PTEN在骨发育中的作用尚不完全清楚。为了确定PTEN在骨发育过程中如何在骨祖细胞中发挥作用，我们使用CRE-deleter菌株Dermo1cre有条件地删除了小鼠的Pten，该菌株针对的是注定要形成骨的未分化间充质。骨祖细胞中Pten基因的缺失导致成骨细胞数量增加和骨基质扩张。值得注意的是，在新生骨领中，成骨细胞的发育和类骨质的合成从通常的骨痂生长板中的紧密连接到软骨细胞的分化是分离的。成骨细胞和成骨前体细胞的扩张是由于成纤维细胞生长因子信号的增强，表现为(1)成骨细胞有丝分裂原FGF18表达增加，(2)成纤维细胞生长因子信号抑制因子SPRY2表达减少。成骨细胞的分化独立于生长板软骨细胞，并与GLI2蛋白水平的增加有关，GLI2是Hedgehog信号的主要中介转录因子。我们提供的证据表明，GLI2活性的增加也是通过需要丝裂原激活的蛋白激酶的下游事件增加的成纤维细胞生长因子信号的结果。为了测试成纤维细胞生长因子受体2(FGFR2)的一个等位基因的缺失是否需要成纤维细胞生长因子信号转导。值得注意的是，FGFR2的缺失导致了Pten零表型的部分挽救。这项研究确认激活的成纤维细胞生长因子信号是骨祖细胞中Pten缺失的主要中介。
Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a direct antagonist of phosphatidylinositol 3 kinase. Pten is a well recognized tumor suppressor and is one of the most commonly mutated genes in human malignancies. More recent studies of development and stem cell behavior have shown that PTEN regulates the growth and differentiation of progenitor cells. Significantly, PTEN is found in osteoprogenitor cells that give rise to bone-forming osteoblasts; however, the role of PTEN in bone development is incompletely understood. To define how PTEN functions in osteoprogenitors during bone development, we conditionally deleted Pten in mice using the cre-deleter strain Dermo1cre, which targets undifferentiated mesenchyme destined to form bone. Deletion of Pten in osteoprogenitor cells led to increased numbers of osteoblasts and expanded bone matrix. Significantly, osteoblast development and synthesis of osteoid in the nascent bone collar was uncoupled from the usual tight linkage to chondrocyte differentiation in the epiphyseal growth plate. The expansion of osteoblasts and osteoprogenitors was found to be due to augmented FGF signaling as evidenced by (1) increased expression of FGF18, a potent osteoblast mitogen, and (2) decreased expression of SPRY2, a repressor of FGF signaling. The differentiation of osteoblasts was autonomous from the growth plate chondrocytes and was correlated with an increase in the protein levels of GLI2, a transcription factor that is a major mediator of hedgehog signaling. We provide evidence that increased GLI2 activity is also a consequence of increased FGF signaling through downstream events requiring mitogen-activated protein kinases. To test whether FGF signaling is required for the effects of Pten deletion, we deleted one allele of fibroblast growth factor receptor 2 (FGFR2). Significantly, deletion of FGFR2 caused a partial rescue of the Pten-null phenotype. This study identifies activated FGF signaling as the major mediator of Pten deletion in osteoprogenitors.