Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells:: the role of PPAR-γ2 transcription factor and TGF-β/BMP signaling pathways
Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells:: the role of PPAR-γ2 transcription factor and TGF-β/BMP signaling pathways
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DOI：
10.1111/j.1474-9728.2004.00127.x
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发表时间：
2004-12-01
期刊：
影响因子：
7.8
通讯作者：
Lecka-Czernik, B
中科院分区：
文献类型：
--
作者：
Moerman, EJ;Teng, K;Lecka-Czernik, B
成骨细胞和脂肪细胞起源于共同的祖细胞，其起源于骨髓间充质基质/干细胞（mMSC）。衰老导致成骨细胞数量减少，骨髓脂肪细胞数量增加。在这里，我们证明，在衰老过程中，mMSC的状态变化，其内在的分化潜力和信号分子的产生，这有助于形成一个特定的骨髓微环境，维持骨稳态所必需的。衰老导致mMSC向成骨细胞谱系的定向减少和向脂肪细胞谱系的定向增加。这通过表型特异性基因标记物表达的变化来反映。成骨细胞特异性转录因子Runx 2和Dlx 5和成骨细胞标志物胶原蛋白和骨钙素的表达在老年mMSC中减少。相反，脂肪细胞特异性转录因子PPAR-gamma 2的表达增加，先前显示负向调节成骨细胞发育和骨形成，并正向调节骨髓脂肪细胞分化，脂肪细胞表型的基因标记物脂肪酸结合蛋白aP 2也是如此。此外，刺激脂肪细胞分化的内源性PPAR-gamma激活剂的产生和抑制成骨细胞表型的自分泌/旁分泌因子的产生也增加。此外，TGF-β和BMP 2/4信号通路的不同组分的表达发生改变，表明这两种对骨稳态至关重要的细胞因子的活性随着年龄的增长而改变。
Osteoblasts and adipocytes originate from a common progenitor, which arises from bone marrow mesenchymal stroma/stem cells (mMSC). Aging causes a decrease in the number of bone-forming osteoblasts and an increase in the number of marrow adipocytes. Here, we demonstrate that, during aging, the status of mMSC changes with respect to both their intrinsic differentiation potential and production of signaling molecules, which contributes to the formation of a specific marrow microenvironment necessary for maintenance of bone homeostasis. Aging causes a decrease in the commitment of mMSC to the osteoblast lineage and an increase in the commitment to the adipocyte lineage. This is reflected by changes in the expression of phenotype-specific gene markers. The expression of osteoblast-specific transcription factors, Runx2 and Dlx5, and osteoblast markers, collagen and osteocalcin, is decreased in aged mMSC. Conversely, the expression of adipocyte-specific transcription factor PPAR-gamma2, shown previously to regulate osteoblast development and bone formation negatively and to regulate marrow adipocyte differentiation positively, is increased, as is a gene marker of adipocyte phenotype, fatty acid binding protein aP2. Furthermore, production of an endogeneous PPAR-gamma activator(s) that stimulates adipocyte differentiation and production of autocrine/paracrine factor(s) that suppresses the osteoblastic phenotype are also increased. in addition, expression of different components of TGF-beta and BMP2/4 signaling pathways is altered, suggesting that activities of these two cytokines essential for bone homeostasis change with aging.