Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification.
Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification.
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DOI：
10.1002/jbmr.481
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发表时间：
2011-11
影响因子：
6.2
通讯作者：
Shore, Eileen M.
中科院分区：
文献类型：
--
作者：
Pignolo, Robert J.;Xu, Meiqi;Russell, Elizabeth;Richardson, Alec;Kaplan, Josef;Billings, Paul C.;Kaplan, Frederick S.;Shore, Eileen M.
关键词：
具有皮下异位骨化（HO）共同特征的人类遗传性疾病是由GNAS的杂合失活突变引起的，GNAS是一种编码多个转录本的基因，包括两种刺激性G蛋白，腺苷酸环化酶的刺激性G蛋白（Gsα）的α亚基和Gsα的“超长”形式XLαs。在一种这样的病症中，进行性骨异型增生（POH），骨形成在进展到更深的组织之前在皮下脂肪内起始，这表明骨生成可能涉及存在于脂肪组织中的间充质前体的异常分化。我们通过免疫组化分析确定GNAS蛋白表达仅限于骨衬里细胞中的Gsα和骨细胞中的Gsα和XLαs。相比之下，在脂肪细胞和脂肪基质中检测到GNAS蛋白Gsα、XLαs和NESP 55。尽管通过qRT-PCR评估的Gnas转录物在骨来源的前体细胞的成骨细胞分化后没有显示出显著变化，但是这些转录物的丰度通过脂肪来源的间充质祖细胞的成骨细胞分化而增强。使用小鼠敲除模型，我们确定Gnas的杂合失活（通过破坏Gsα特异性外显子1）消除了多种Gnas转录物的上调，这种上调通常发生在野生型脂肪基质细胞中的成骨细胞分化中。Gnas+/−小鼠中的这些转录变化伴随着体外脂肪基质细胞的加速成骨细胞分化。在体内，Gnas+/−小鼠中改变的成骨细胞分化通过膜内过程表现为皮下HO。总之，这些数据表明，Gnas是脂肪来源的间充质祖细胞，特别是那些参与骨形成的细胞命运决定的关键调节因子。
Human genetic disorders sharing the common feature of subcutaneous heterotopic ossification (HO) are caused by heterozygous inactivating mutations in GNAS, a gene encoding multiple transcripts including two stimulatory G-proteins, the α-subunit of the stimulatory G-protein (Gsα) of adenylyl cyclase and the ‘extra-long” form of Gsα, XLαs. In one such disorder, progressive osseous heteroplasia (POH), bone formation initiates within subcutaneous fat before progressing to deeper tissues, suggesting that osteogenesis may involve abnormal differentiation of mesenchymal precursors that are present in adipose tissues. We determined by immunohistochemical analysis that GNAS protein expression is limited to Gsα in bone-lining cells and to Gsα and XLαs in osteocytes. By contrast, the GNAS proteins Gsα, XLαs, and NESP55 are detected in adipocytes and in adipose stroma. Although Gnas transcripts, as assessed by qRT-PCR, show no significant changes upon osteoblast differentiation of bone-derived precursor cells, the abundance of these transcripts is enhanced by osteoblast differentiation of adipose-derived mesenchymal progenitors. Using a mouse knockout model, we determined that heterozygous inactivation of Gnas (by disruption of the Gsα-specific exon 1) abrogates upregulation of multiple Gnas transcripts that normally occurs with osteoblast differentiation in wild-type adipose stromal cells. These transcriptional changes in Gnas+/− mice are accompanied by accelerated osteoblast differentiation of adipose stromal cells in vitro. In vivo, altered osteoblast differentiation in Gnas+/− mice manifests as subcutaneous HO by an intramembranous process. Taken together, these data suggest that Gnas is a key regulator of fate decisions in adipose-derived mesenchymal progenitor cells, specifically those that are involved in bone formation.
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影响因子：
2
作者：
Adegbite, N. S.;Xu, M.;Kaplan, F. S.;Shore, E. M.;Pignolo, R. J.
通讯作者：
Pignolo, R. J.
影响因子：
158.5
作者：
Shore, EM;Ahn, J;Kaplan, FS
通讯作者：
Kaplan, FS
影响因子：
7.8
作者：
Pignolo, Robert J.;Suda, Robin K.;Johnson, F. Brad
通讯作者：
Johnson, F. Brad
影响因子：
82.9
作者：
Sabatakos, G;Sims, NA;Baron, R
通讯作者：
Baron, R
DOI：
10.1073/pnas.95.26.15475
发表时间：
1998-12-22
影响因子：
11.1
作者：
Hayward, BE;Moran, V;Bonthron, DT
通讯作者：
Bonthron, DT