Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany.
PLoS One. 2012;7(9):e45142. doi: 10.1371/journal.pone.0045142. Epub 2012 Sep 24.
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.
原发性骨质疏松症是一种与年龄相关的疾病，其特征是骨稳态失衡。虽然该疾病的吸收方面已经得到了深入研究，但对综合征的合成部分或假定的骨再生缺陷知之甚少。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学，因此对患有骨质疏松症的老年患者（79-94 岁）的 hMSC 进行了微阵列分析（hMSC-OP）。与年龄匹配的对照组相比，我们在 hMSC-OP 中检测到转录组的深刻变化，例如已知与骨质疏松症相关的基因（LRP5、RUNX2、COL1A1）和破骨细胞生成相关基因（CSF1、PTH1R）的 mRNA 表达增强，但最显着的是编码 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症干细胞在自我更新和分化潜能方面存在内在缺陷。我们还将 hMSC-OP 和老年供体的非骨质疏松 hMSC-old 与约 30 岁以下供体的 hMSC 进行了比较，发现第六和第九个十年之间获得的转录变化在骨质疏松症和非骨质疏松症干细胞之间差异很大。此外，我们将骨质疏松症转录组与长期培养的衰老 hMSC 进行了比较，并在 hMSC-OP 中检测到一些衰老前的迹象。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独特的特征，与非骨质疏松性衰老几乎没有重叠，尽管我们检测到一些与衰老相关变化的迹象。虽然存在多基因疾病所预期的显着个体间变异，但我们可以从遗传研究中识别出许多骨质疏松症的易感基因。我们还发现了一些新的候选基因，例如 MAB21L2，这是一种新的 BMP 诱导转录抑制剂。这种转录变化可能反映了表观遗传变化，这是特定骨质疏松症相关衰老过程的一部分。
