The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors.
The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors.
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DOI：
10.1371/journal.pone.0045142
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jakob F
中科院分区：
文献类型：
--
作者：
Benisch P;Schilling T;Klein-Hitpass L;Frey SP;Seefried L;Raaijmakers N;Krug M;Regensburger M;Zeck S;Schinke T;Amling M;Ebert R;Jakob F
原发性骨质疏松症是一种与年龄有关的疾病，其特征是骨骼平衡失衡。虽然该疾病的吸收方面已被深入研究，但对该综合征的合成代谢部分或骨再生的推定缺陷知之甚少。多能间充质干细胞（MSC）是成骨再生的主要来源。在本研究中，我们旨在揭示MSC生物学是否直接参与疾病的病理生理，因此对老年骨质疏松症（hMSC- op）患者的hMSC进行了微阵列分析。与年龄匹配的对照组相比，我们发现hMSC-OP的转录组发生了深刻的变化，例如，已知的骨质疏松相关基因（LRP5, RUNX2, COL1A1）和参与破骨细胞发生的基因（CSF1, PTH1R）的mRNA表达增强，但最值得注意的是编码WNT和BMP信号抑制剂的基因，如Sclerostin和MAB21L2。这些候选基因表明骨质疏松干细胞在自我更新和分化潜能方面存在内在缺陷。我们还比较了老年供者的hMSC- op和非骨质疏松性hMSC-old与30岁左右的年轻供者的hMSC，发现骨质疏松性和非骨质疏松性干细胞在生命的第6和第9个十年之间获得的转录变化差异很大。此外，我们将骨质疏松的转录组与长期培养的衰老hMSC进行比较，并在hMSC- op中检测到一些早衰老的迹象。我们的研究结果表明，在原发性骨质疏松症中，hMSC群体的转录组显示出明显的特征，与非骨质疏松性衰老几乎没有重叠，尽管我们发现了一些衰老相关变化的线索。虽然多遗传疾病存在显著的个体间差异，但我们可以从遗传研究中确定许多骨质疏松症的易感基因。我们还发现了新的候选药物，例如MAB21L2，一种新的bmp诱导转录抑制因子。这种转录变化可能反映了表观遗传变化，这是骨质疏松症相关衰老过程的一部分。
Primary osteoporosis is an age-related disease characterized by an imbalance in bone homeostasis. While the resorptive aspect of the disease has been studied intensely, less is known about the anabolic part of the syndrome or presumptive deficiencies in bone regeneration. Multipotent mesenchymal stem cells (MSC) are the primary source of osteogenic regeneration. In the present study we aimed to unravel whether MSC biology is directly involved in the pathophysiology of the disease and therefore performed microarray analyses of hMSC of elderly patients (79–94 years old) suffering from osteoporosis (hMSC-OP). In comparison to age-matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2. These candidate genes indicate intrinsic deficiencies in self-renewal and differentiation potential in osteoporotic stem cells. We also compared both hMSC-OP and non-osteoporotic hMSC-old of elderly donors to hMSC of ∼30 years younger donors and found that the transcriptional changes acquired between the sixth and the ninth decade of life differed widely between osteoporotic and non-osteoporotic stem cells. In addition, we compared the osteoporotic transcriptome to long term-cultivated, senescent hMSC and detected some signs for pre-senescence in hMSC-OP. Our results suggest that in primary osteoporosis the transcriptomes of hMSC populations show distinct signatures and little overlap with non-osteoporotic aging, although we detected some hints for senescence-associated changes. While there are remarkable inter-individual variations as expected for polygenetic diseases, we could identify many susceptibility genes for osteoporosis known from genetic studies. We also found new candidates, e.g. MAB21L2, a novel repressor of BMP-induced transcription. Such transcriptional changes may reflect epigenetic changes, which are part of a specific osteoporosis-associated aging process.
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DOI：
10.1083/jcb.201008012
发表时间：
2011-03-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Albers J;Schulze J;Beil FT;Gebauer M;Baranowsky A;Keller J;Marshall RP;Wintges K;Friedrich FW;Priemel M;Schilling AF;Rueger JM;Cornils K;Fehse B;Streichert T;Sauter G;Jakob F;Insogna KL;Pober B;Knobeloch KP;Francke U;Amling M;Schinke T
通讯作者：
Schinke T
影响因子：
8
作者：
Dalvai, M.;Mondesert, O.;Dozier, C.
通讯作者：
Dozier, C.
影响因子：
--
作者：
Carbonare, Luca Dalle;Valenti, Maria Teresa;Lo Cascio, Vincenzo
通讯作者：
Lo Cascio, Vincenzo
影响因子：
4
作者：
Canalis, Ernesto
通讯作者：
Canalis, Ernesto
影响因子：
4.8
作者：
Devlin, RD;Du, Z;Canalis, E
通讯作者：
Canalis, E