Muenke Syndrome Mutation, FgfR3P244R, Causes TMJ Defects
Muenke Syndrome Mutation, FgfR3P244R, Causes TMJ Defects
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DOI：
10.1177/0022034512449170
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发表时间：
2012-05
影响因子：
7.6
通讯作者：
T. Yasuda;T. Yasuda;H. Nah;J. Laurita;T. Kinumatsu;Yoshihiro Shibukawa;Toshiaki Shibutani;Nancy Minugh-Purvis;Maurizio Pacifici;E. Koyama
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文献类型：
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作者：
T. Yasuda;T. Yasuda;H. Nah;J. Laurita;T. Kinumatsu;Yoshihiro Shibukawa;Toshiaki Shibutani;Nancy Minugh-Purvis;Maurizio Pacifici;E. Koyama
Muenke综合征以各种颅面畸形为特征，由成纤维细胞生长因子受体3 （FGFR3P250R）的常染色体显性激活突变引起。在这里，我们使用携带相应突变（FgfR3P244R）的小鼠，确定该突变是否影响颞下颌关节（TMJ）的发育和生长。原位杂交显示，FgfR3在髁状软骨祖细胞和成熟软骨细胞中表达，这些细胞也表达印度hedgehog （Ihh）受体和转录靶点Patched 1（Ptch1）。在FgfR3P244R突变体中，髁突显示Ihh表达水平降低，h4c阳性增殖软骨祖细胞以及表达II型和x型胶原的软骨细胞水平降低。原发性海绵状骨形成也受到干扰，并伴有破骨细胞活性增加和小梁骨形成减少。用重组FGF2/FGF9处理野生型髁外植体，可降低表面/多态层Ptch1和PTHrP的表达以及软骨祖细胞的增殖。我们还观察到髁状关节软骨的早期退行性改变，TMJ关节隆起/关节盂窝的异常发育以及关节盘的融合。我们的数据分析表明，激活FgfR3P244R突变可能通过减少hedgehog信号和软骨内成骨来干扰TMJ的发育过程。我们认为FGF和hedgehog信号通路之间的平衡对于TMJ发育的完整性和细胞组织的维持至关重要。
Muenke syndrome is characterized by various craniofacial deformities and is caused by an autosomal-dominant activating mutation in fibroblast growth factor receptor 3 (FGFR3P250R). Here, using mice carrying a corresponding mutation (FgfR3P244R), we determined whether the mutation affects temporomandibular joint (TMJ) development and growth. In situ hybridization showed that FgfR3 was expressed in condylar chondroprogenitors and maturing chondrocytes that also expressed the Indian hedgehog (Ihh) receptor and transcriptional target Patched 1(Ptch1). In FgfR3P244R mutants, the condyles displayed reduced levels of Ihh expression, H4C-positive proliferating chondroprogenitors, and collagen type II- and type X-expressing chondrocytes. Primary bone spongiosa formation was also disturbed and was accompanied by increased osteoclastic activity and reduced trabecular bone formation. Treatment of wild-type condylar explants with recombinant FGF2/FGF9 decreased Ptch1 and PTHrP expression in superficial/polymorphic layers and proliferation in chondroprogenitors. We also observed early degenerative changes of condylar articular cartilage, abnormal development of the articular eminence/glenoid fossa in the TMJ, and fusion of the articular disc. Analysis of our data indicates that the activating FgfR3P244R mutation disturbs TMJ developmental processes, likely by reducing hedgehog signaling and endochondral ossification. We suggest that a balance between FGF and hedgehog signaling pathways is critical for the integrity of TMJ development and for the maintenance of cellular organization.