TMJ Development and Growth Require Primary Cilia Function
TMJ Development and Growth Require Primary Cilia Function
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DOI：
10.1177/0022034511409407
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发表时间：
2011-08-01
影响因子：
7.6
通讯作者：
Koyama, E.
中科院分区：
文献类型：
--
作者：
Kinumatsu, T.;Shibukawa, Y.;Koyama, E.
初级纤毛调节肢体和轴向骨骼的形成和刺猬信号，但其在颞下颌关节（TMJ）发育中的作用尚不清楚。因此，我们创建了软骨中纤毛转运蛋白Kif 3a缺陷的条件小鼠突变体。在出生后的野生型小鼠，初级纤毛偶尔观察到髁突细胞的上级，下部，或外侧。纤毛在突变软骨细胞中几乎检测不到，但在周围组织中很明显，证明了软骨细胞Kif 3a消融的特异性。3月龄小鼠的突变髁状突沿其前后轴和内外轴沿着狭窄平坦，通常与关节盘融合，并显示不规则的骨表面。P15突变体中的多态性层含有较少的Sox 9表达软骨祖细胞，因为有丝分裂活性降低，新分化的软骨细胞经历了早熟肥大性扩大伴随着早期激活的印度刺猬（Ihh）。有趣的是，沿着软骨膜存在过度的膜内骨化沿着，伴随着hedgehog受体Patched-1的局部表达以及Osterix和胶原I的上调。总之，Kif 3a和初级纤毛是协调软骨细胞成熟、膜内骨形成和软骨形成髁突生长所必需的。Kif 3a髁突软骨中这些过程的缺陷可能反映了异常的刺猬信号拓扑结构和功能障碍。
Primary cilia regulate limb and axial skeletal formation and hedgehog signaling, but their roles in temporomandibular joint (TMJ) development are unknown. Thus, we created conditional mouse mutants deficient in ciliary transport protein Kif3a in cartilage. In post-natal wildtype mice, primary cilia were occasionally observed on the superior, inferior, or lateral side of condylar cells. Cilia were barely detectable in mutant chondrocytes but were evident in surrounding tissues, attesting to the specificity of chondrocyte Kif3a ablation. Mutant condyles from 3-month-old mice were narrow and flat along their antero-posterior and medio-lateral axes, were often fused with the articular disc, and displayed an irregular bony surface. The polymorphic layer in P15 mutants contained fewer Sox9-expressing chondroprogenitor cells because of reduced mitotic activity, and newly differentiated chondrocytes underwent precocious hypertrophic enlargement accompanied by early activation of Indian hedgehog (Ihh). Interestingly, there was excessive intramembranous ossification along the perichondrium, accompanied by local expression of the hedgehog receptor Patched-1 and up-regulation of Osterix and Collagen I. In summary, Kif3a and primary cilia are required for coordination of chondrocyte maturation, intramembranous bone formation, and chondrogenic condylar growth. Defects in these processes in Kif3a condylar cartilage are likely to reflect abnormal hedgehog signaling topography and dysfunction.