Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs).
Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs).
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Sox9 通过下调间充质干细胞 (MSC) 中的 Smad7 增强 BMP2 诱导的软骨形成分化。
DOI：
10.1016/j.gendis.2017.10.004
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发表时间：
2017-12
期刊：
影响因子：
6.8
通讯作者：
Huang W
中科院分区：
文献类型：
--
作者：
Zhao C;Jiang W;Zhou N;Liao J;Yang M;Hu N;Liang X;Xu W;Chen H;Liu W;Shi LL;Oliveira L;Wolf JM;Ho S;Athiviraham A;Tsai HM;He TC;Huang W
由于软骨细胞固有的增殖能力有限，关节炎或创伤引起的软骨损伤对有效的临床治疗提出了巨大的挑战。自体干细胞疗法和转基因增强的软骨组织工程可能为软骨损伤的治疗开辟新的途径。骨形态发生蛋白2（BMP 2）诱导间充质干细胞（MSCs）有效的软骨形成，因此可以探索作为软骨缺损修复的潜在治疗剂。然而，BMP 2也诱导稳健的软骨内骨化。尽管BMP 2调控软骨发生和成骨分化的确切机制仍有待充分理解，但在BMP 2诱导的软骨形成过程中阻断软骨内骨化可能对软骨组织工程具有实际意义。在此，我们研究了Sox 9-don调节的Smad 7在BMP 2诱导的MSCs软骨分化中的作用。我们发现Sox 9的过表达导致骨髓间充质干细胞中BMP 2诱导的Smad 7表达减少。Sox 9抑制BMP 2诱导的骨桥蛋白表达，同时增强MSC中软骨形成标记物Col 2a 1的表达。Sox 9在MSCs中的强制表达促进BMP 2诱导的软骨形成并抑制BMP 2诱导的软骨内骨化。组成型Smad 7表达在干细胞植入试验中抑制BMP 2诱导的软骨形成。小鼠肢体移植实验表明，Sox 9扩大BMP 2刺激的软骨细胞增殖区，而Smad 7促进BMP 2启动的生长板肥大区。细胞周期分析表明，Smad 7诱导BMP 2刺激的MSC的显着的早期凋亡。总之，我们的研究结果强烈表明，Sox 9可能通过下调Smad 7促进BMP 2诱导的软骨形成，这可以用于有效的软骨组织工程。
Cartilage injuries caused by arthritis or trauma pose formidable challenges for effective clinical management due to the limited intrinsic proliferative capability of chondrocytes. Autologous stem cell-based therapies and transgene-enhanced cartilage tissue engineering may open new avenues for the treatment of cartilage injuries. Bone morphogenetic protein 2 (BMP2) induces effective chondrogenesis of mesenchymal stem cells (MSCs) and can thus be explored as a potential therapeutic agent for cartilage defect repair. However, BMP2 also induces robust endochondral ossification. Although the precise mechanisms through which BMP2 governs the divergence of chondrogenesis and osteogenesis remain to be fully understood, blocking endochondral ossification during BMP2-induced cartilage formation may have practical significance for cartilage tissue engineering. Here, we investigate the role of Sox9-donwregulated Smad7 in BMP2-induced chondrogenic differentiation of MSCs. We find that overexpression of Sox9 leads to a decrease in BMP2-induced Smad7 expression in MSCs. Sox9 inhibits BMP2-induced expression of osteopontin while enhancing the expression of chondrogenic marker Col2a1 in MSCs. Forced expression of Sox9 in MSCs promotes BMP2-induced chondrogenesis and suppresses BMP2-induced endochondral ossification. Constitutive Smad7 expression inhibits BMP2-induced chondrogenesis in stem cell implantation assay. Mouse limb explant assay reveals that Sox9 expands BMP2-stimulated chondrocyte proliferating zone while Smad7 promotes BMP2-intitated hypertrophic zone of the growth plate. Cell cycle analysis indicates that Smad7 induces significant early apoptosis in BMP2-stimulated MSCs. Taken together, our results strongly suggest that Sox9 may facilitate BMP2-induced chondrogenesis by downregulating Smad7, which can be exploited for effective cartilage tissue engineering.
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影响因子：
3.7
作者：
Deng F;Chen X;Liao Z;Yan Z;Wang Z;Deng Y;Zhang Q;Zhang Z;Ye J;Qiao M;Li R;Denduluri S;Wang J;Wei Q;Li M;Geng N;Zhao L;Zhou G;Zhang P;Luu HH;Haydon RC;Reid RR;Yang T;He TC
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5.1
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通讯作者：
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影响因子：
2.8
作者：
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影响因子：
6.2
作者：
Huang, Enyi;Zhu, Gaohui;He, Tong-Chuan
通讯作者：
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影响因子：
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作者：
Ikeda, T;Kamekura, S;Chung, UI
通讯作者：
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