LMP1 regulates periodontal ligament progenitor cell proliferation and differentiation.
LMP1 regulates periodontal ligament progenitor cell proliferation and differentiation.
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DOI：
10.1016/j.bone.2010.03.013
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发表时间：
2010-07
期刊：
影响因子：
4.1
通讯作者：
Giannobile, William V.
中科院分区：
文献类型：
--
作者：
Lin, Zhao;Navarro, Valeria Pontelli;Kempeinen, Kathryn M.;Franco, Leo M.;Jin, Qiming;Sugai, James V.;Giannobile, William V.
LMP 1是一种细胞内支架蛋白，含有一个PDZ结构域和三个LIM结构域。LMP 1具有多种功能，包括调节间充质干细胞（MSC）成骨。LMP 1的基因递送在体内异位和原位位点诱导骨形成。然而，在分子水平上对LMP 1在MSC中的生理功能和基因调控机制知之甚少。牙周膜韧带（PDL）细胞是一种独特的祖细胞群，可以分化成多种细胞类型，包括成骨细胞，脂肪细胞或软骨细胞。本研究旨在从分子水平探讨LMP 1在PDL细胞中的生理功能和基因调控机制。我们发现LMP 1在PDL细胞成骨分化的早期阶段上调。通过shRNA稳定敲除LMP 1基因抑制PDL细胞的DNA合成和相应的细胞增殖，并进一步导致体外矿化减少。LMP 1的过表达增加细胞增殖，PDZ和www相互作用结构域不足以介导这种作用。此外，我们发现在PDL细胞中，LMP 1是TGF-β1的下游靶基因，TGF-β1是前成骨细胞增殖和分化的早期关键信号。TGF-β1刺激PDL细胞增殖，然而，当LMP 1被敲低时，这种作用被削弱。我们进一步证实了TAK 1-JNK/p38激酶级联的激活参与了TGF-β1对LMP 1基因的调控。结论：LMP 1是TGF-β1的下游基因，参与PDL细胞增殖。我们的研究结果推进了对LMP 1生理功能的理解，并确定了LMP 1在PDL祖细胞和其他MSC中的调节机制。
LMP1 is an intracellular scaffold protein that contains a PDZ domain and three LIM domains. LMP1 has multiple functions including regulating mesenchymal stem cell (MSC) osteogenesis. Gene delivery of LMP1 induces bone formation in vivo in heterotopic and orthotopic sites. However, little is known about the physiological function and gene regulatory mechanisms of LMP1 in MSCs at the molecular level. Periodontal ligament (PDL) cells are a unique progenitor cell population that can differentiate into multiple cell types, including osteoblasts, adipocytes or chondrocytes. This study sought to determine the physiological function and gene regulatory mechanisms of LMP1 in PDL cells at the molecular level. We show that LMP1 is upregulated in early stage of PDL cell osteogenic differentiation. Stable gene knockdown of LMP1 by shRNA inhibits DNA synthesis and corresponding cell proliferation in PDL cells, and further leads to decreased mineralization in vitro. Overexpression of LMP1 increases cell proliferation, and PDZ and ww-interacting domains are not enough to mediate this effect. Further, we found that in PDL cells, LMP1 is a downstream target gene of TGF-β1 that is an early signal critical in preosteoblast proliferation and differentiation. TGF-β1 stimulates PDL cell proliferation, however, this effect is compromised when LMP1 is knocked down. We further identified that the activation of TAK1-JNK/p38 kinase cascade is involved in the LMP1 gene regulation by TGF-β1. We conclude that LMP1 is a downstream gene of TGF-β1, involved in PDL cell proliferation. Our findings advance the understanding of the physiological function of LMP1, and define a regulatory mechanism of LMP1 in PDL progenitor cells and other MSCs.
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