Aïoub M, Lézot F, Molla M, Castaneda B, Robert B, Goubin G, Néfussi J R, Berdal A
INSERM, UMR S 872, Les Cordeliers, F-75006, Paris, France.
Bone. 2007 Nov;41(5):851-9. doi: 10.1016/j.bone.2007.07.023. Epub 2007 Aug 15.
The physiological function of the transcription factor Msx2 in tooth and alveolar bone was analysed using a knock-in transgenic mouse line. In this mouse line, the beta-galactosidase gene was used to disrupt Msx2: thus, beta-galactosidase expression was driven by the Msx2 promoter, but Msx2 was not produced. This allowed to monitor Msx2 expression using a beta-galactosidase assay. Msx2 transgenic mice ubiquitously and continuously expressed the mutated Msx2-nlacZ gene in cells of the complex formed by tooth and alveolar bone. Msx2 -/- homozygous mice displayed a wide spectrum of alterations in tooth eruption and morphology as well as dental and periodontal defects from the first post-natal weeks up to 6 months. These defects culminated with the formation of an odontogenic tumour at the mandibular third molar site. This study suggests that bone resorption is a functional target of Msx2 in the alveolar compartment, since Msx2 was expressed in osteoclasts, with the highest expression levels found in the active sites of bone modelling associated with tooth eruption and root elongation. The RANK osteoclast differentiation pathway was affected in microdissected Msx2 -/- mouse alveolar bone (as inferred by RANK ligand mRNA levels) compared to basal bone and wild-type controls. Decreased alveolar osteoclast activity was observed in Msx2 -/- mice, similar to that seen in osteopetrosis, another condition in which osteoclast activity is impaired and odontogenic tumours form. These data suggest a pleiotropic role for Msx2 in oral bone growth from birth until adult homeostasis. RANK pathway appeared to be modulated by Msx2, in addition to the previously reported modulations of BMP4 and laminin5alpha3 in early tooth development. Non-overlapping Msx1 and Msx2 expression patterns suggested that these two homeogenes play non-redundant roles in skeletal growth, with Msx1 targeting basal bone and Msx2 targeting alveolar bone. This study provides a detailed analysis of the phenotype resulting from the Msx2 null mutation and identifies the impact of Msx1 and Msx2 on post-natal oral bone growth.
利用一种敲入转基因小鼠品系分析了转录因子Msx2在牙齿和牙槽骨中的生理功能。在这个小鼠品系中，β-半乳糖苷酶基因被用于破坏Msx2：因此，β-半乳糖苷酶的表达由Msx2启动子驱动，但不产生Msx2。这使得能够使用β-半乳糖苷酶检测来监测Msx2的表达。Msx2转基因小鼠在由牙齿和牙槽骨形成的复合体的细胞中普遍且持续地表达突变的Msx2-nlacZ基因。Msx2 -/-纯合小鼠从出生后第一周直至6个月，在牙齿萌出和形态以及牙齿和牙周方面表现出广泛的改变。这些缺陷最终在下颌第三磨牙部位形成牙源性肿瘤。这项研究表明骨吸收是Msx2在牙槽隔中的一个功能靶点，因为Msx2在破骨细胞中表达，在与牙齿萌出和牙根伸长相关的骨重塑活跃部位发现其表达水平最高。与基础骨和野生型对照相比，在显微解剖的Msx2 -/-小鼠牙槽骨中RANK破骨细胞分化途径受到影响（通过RANK配体mRNA水平推断）。在Msx2 -/-小鼠中观察到牙槽破骨细胞活性降低，类似于骨硬化症中的情况，骨硬化症是另一种破骨细胞活性受损且形成牙源性肿瘤的病症。这些数据表明Msx2在从出生到成年稳态的口腔骨生长中具有多效性作用。除了先前报道的在早期牙齿发育中Msx2对BMP4和层粘连蛋白5α3的调节作用外，RANK途径似乎也受Msx2调节。不重叠的Msx1和Msx2表达模式表明这两个同源基因在骨骼生长中发挥非冗余作用，Msx1作用于基础骨，Msx2作用于牙槽骨。这项研究对Msx2无效突变导致的表型进行了详细分析，并确定了Msx1和Msx2对出生后口腔骨生长的影响。
