Role of Mkx (Mohawk) in tendon tissue engineering

doi:10.3969/j.issn.2095-4344.2016.37.016

Abstract

Abstract:

BACKGROUND: Mkx (Mohawk, transcription factor) is one of the crucial factors in tendon formation, development and differentiation.
OBJECTIVE: To summarize the molecular structure, distribution and function of Mkx and its research process in the signaling pathways during tendon differentiation.
METHODS: The first author retrieved the databases of CqVip, CNKI and Medline from1990 to 2016 using the keywords of “Mkx, Mohawk, Irxl, tendon, tendon differentiation, tissue engineering, TGFβ, stem cell” in Chinese and English, respectively. The articles related to research process of Mkx in tendon tissue engineering were retrieved, and a total of 55 literatures were enrolled finally.
RESULTS AND CONCLUSION: Mkx that expresses in various mesoderm-derived tissues plays an important role in the formation and development of tendon and tissue-engineered tendon formation. Although Mkx does not directly act on Scx (Scleraxis), it can regulate the differentiation of tendon progenitor cells via transforming growth factor-β2 signaling pathway. Cells from different species and different cell lines as well as various cytokines for certain make different effects on Mkx involved in tendon tissue engineering.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Tendons, Stem Cells, Transcription Factors

CLC Number:

R318

Li Dan, Guo Xing, Tan Mei-yun. Role of Mkx (Mohawk) in tendon tissue engineering[J]. Chinese Journal of Tissue Engineering Research, 2016, 20(37): 5580-5587.

Figures/Tables 1

2.1 Mkx的结构、分布和功能 2.1.1 Mkx的结构 kx(Mohawk)又称为Irxl(Iroquois home0box-like，Irxl)[18]，是三氨基环酸(three- amino-acid loop，TALE)超家族的成员之一。Mkx是肌腱发育过程中肌腱细胞所表达的非典型的同源异型盒基因，在许多组织器官发育过程中都是必要的，包括细胞的增殖、分化等过程[19-23]。Mkx具有转录抑制活性[24-25]，且包括了3个小阻遏域。Mkx作为一个转录抑制因子，是通过招募Sin3A /DHAC抑制复合物而发挥作用的[24]。Mkx基因可编码353个氨基酸，它在多种中胚层来源的组织细胞中表达。Irxl1与Iroquois家族基因最相似，但在所有的Irx基因中缺乏典型的IRO盒[26-27]。在许多脊椎动物和无脊椎动物物种中均发现了Mkx，Mkx与脊椎动物同源基因含有同源结构域的同源性为100%[28]。 2.1.2 Mkx的分布与功能 Mkx在肌肉骨骼系统、肌肉、软骨、骨及肌腱中均有表达[26-27]。Mkx基因突变小鼠并没有出现明显的软骨、骨或骨骼肌的缺失，反而肌腱发生了严重发育不全[18，29-30]。Mkx-缺失的肌腱I型胶原生成减少，而细胞数目未发生改变。所以，Mkx基因的正常表达是轴向和四肢肌腱的形态和功能保持完整的必需条件。研究发现，体节的生骨节的肌腱祖细胞于E9.5 d出现Scleraxis(Scx)，而在E12.5 d开始出现Mkx，Mkx的表达量较少，而肌腱祖细胞从聚集到分化(E13.5 d- E14.5 d)发现Mkx的表达量明显变多。然而，在出生以后Mkx的表达量明显比胚胎期减少。令人意外的是，Mkx在其四肢及尾部的肌腱鞘中表达量却相对较高[18，30]。最近研究也得出相似结果，分别从胚胎期的整个胚胎、前肢及后肢中提取Mkx，从E10.5 d至E13.5 d发现其在前肢和后肢的肌腱祖细胞中Mkx的表达呈现稳定增长的趋势，而在大鼠出生后4-14 d期间跟腱中的Mkx呈高度表达[17]。由此可以看出，Mkx在肌腱祖细胞的分化过程发挥重要作用，且Mkx参与肢体和肌腱发育的特定阶段。为研究Mkx在体内的功能，Ito等[29]运用了Mkx-/-小鼠进行试验，研究发现小鼠体内形成了发育不全的肌腱，且在这些肌腱中Ⅰ型胶原的表达下调、胶原纤维直径变小。在Mkx基因过表达实验组中发现其肌腱胶原沉积更多、分化更成熟、平均直径更大、直径范围更广，且其力学性能更好[17]。因此，可看出Mkx基因在肌腱的发育过程中是不可或缺的部分，且是肌腱维持其弹性的重要成分。 Onizuka等[31]通过对基因靶向作用的小鼠的研究发现Mkx不仅可调节肌腱分化，而且对腱周组织掌板的发育和平衡也起着重要作用。掌板有胶原纤维束的具体定位，研究者认为其能够抵抗过伸和扭转应变产生的紧张[32]。Onizuka等[31]研究结果发现，在Mkx-裸鼠的掌板中发现杂乱无章排列的纤维，且掌板过伸和侧扭应变时容易受伤，从而引起指骨背侧脱位或大关节不稳。掌板示意图见图2。"

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