Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation.
Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation.
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DOI：
10.1055/s-0032-1321845
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Shore EM
中科院分区：
文献类型：
--
作者：
Zhang S;Kaplan FS;Shore EM
进行性骨异型增生 (POH) 和纤维性发育不良 (FD) 是成骨谱两端骨形成的遗传性疾病：FD 发生骨骼成骨不完善，而 POH 则形成皮肤、皮下脂肪和骨骼肌的异位骨化。 POH 是由 GNAS 中的杂合失活种系突变引起的，GNAS 编码调节 cAMP 通路的 G 蛋白亚基，而 FD 是由 GNAS 体细胞激活突变引起的。我们使用多能小鼠 ES 细胞来检查 Gnas 失调对成骨细胞分化的影响。在成骨的最早阶段，Gnas 转录物 Gs α、XLαs 和 1A 表达水平较低，cAMP 水平也较低。 2',5'-双脱氧腺苷抑制 cAMP 信号（如 POH）可增强成骨细胞分化，相反，毛喉素诱导的 cAMP 信号增强（如 FD）会抑制成骨细胞分化。值得注意的是，增加的 cAMP 仅在成骨诱导后的早期阶段抑制成骨。成骨和脂肪形成标志物的表达表明，即使在成骨因子存在的情况下，cAMP 的增加也会增强脂肪生成并损害成骨细胞分化，这支持 cAMP 作为成骨细胞和脂肪细胞谱系定向的关键调节剂。此外，增加的cAMP信号传导降低了BMP通路信号传导，表明G蛋白-cAMP通路激活（如在FD中）抑制成骨细胞分化，至少部分通过阻断BMP-Smad通路，并表明POH中发生的GNAS失活至少部分通过刺激BMP信号通路增强成骨细胞分化。这些数据支持细胞分化早期阶段 cAMP 水平的差异调节细胞命运决定。
Progressive osseous heteroplasia (POH) and fibrous dysplasia (FD) are genetic diseases of bone formation at opposite ends of the osteogenic spectrum: imperfect osteogenesis of the skeleton occurs in FD, while heterotopic ossification in skin, subcutaneous fat, and skeletal muscle forms in POH. POH is caused by heterozygous inactivating germline mutations in GNAS, which encodes G-protein subunits regulating the cAMP pathway, while FD is caused by GNAS somatic activating mutations. We used pluripotent mouse ES cells to examine the effects of Gnas dysregulation on osteoblast differentiation. At the earliest stages of osteogenesis, Gnas transcripts Gs α, XLαs and 1A are expressed at low levels and cAMP levels are also low. Inhibition of cAMP signaling (as in POH) by 2′,5′-dideoxyadenosine enhanced osteoblast differentiation while conversely, increased cAMP signaling (as in FD), induced by forskolin, inhibited osteoblast differentiation. Notably, increased cAMP was inhibitory for osteogenesis only at early stages after osteogenic induction. Expression of osteogenic and adipogenic markers showed that increased cAMP enhanced adipogenesis and impaired osteoblast differentiation even in the presence of osteogenic factors, supporting cAMP as a critical regulator of osteoblast and adipocyte lineage commitment. Furthermore, increased cAMP signaling decreased BMP pathway signaling, indicating that G protein-cAMP pathway activation (as in FD) inhibits osteoblast differentiation, at least in part by blocking the BMP-Smad pathway, and suggesting that GNAS inactivation as occurs in POH enhances osteoblast differentiation, at least in part by stimulating BMP signaling. These data support that differences in cAMP levels during early stages of cell differentiation regulate cell fate decisions.
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