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Abstract：
Cranial base bones are formed through endochondral ossification. Synchondroses are growth plates located between cranial base bones that facilitate anterior-posterior growth of the skull. Coordinated proliferation and differentiation of chondrocytes in cranial base synchondroses is essential for cranial base bone growth. Herein, we report that constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling via Tsc1 (Tuberous sclerosis 1) deletion in chondrocytes causes abnormal skull development with decreased size and rounded shape. In contrast to decreased anterior-posterior growth of the cranial base, mutant mice also exhibited significant expansion of cranial base synchondroses including the intersphenoid synchondrosis (ISS) and the spheno-occipital synchondrosis (SOS). Cranial base synchondrosis expansion in TSC1-deficient mice was accounted for by an expansion of the resting zone due to increased cell number and size without alteration in cell proliferation. Furthermore, our data showed that mTORC1 activity is inhibited in the resting and proliferating zone chondrocytes of wild type mice, and Tsc1 deletion activated mTORC1 signaling of the chondrocytes in the resting zone area. Consequently, the chondrocytes in the resting zone of TSC1-deficient mice acquired characteristics generally attributed to pre-hypertrophic chondrocytes including high mTORC1 activity, increased cell size, and increased expression level of PTH1R (Parathyroid hormone 1 receptor) and IHH (Indian hedgehog). Lastly, treatment with rapamycin, an inhibitor of mTORC1, rescued the abnormality in synchondroses. Our results established an important role for TSC1-mTORC1 signaling in regulating cranial base bone development and showed that chondrocytes in the resting zone of synchondroses are maintained in an mTORC1-inhibitory environment.
摘要：
颅骨基骨是通过软骨内骨化形成的。合成软骨是位于颅底骨之间的生长板，可促进颅骨的前后生长。颅底联合软骨中软骨细胞的协调增殖和分化对于颅底骨生长至关重要。在这里，我们报告说，通过软骨细胞中Tsc1（结节性硬化症1）缺失，雷帕霉素复合物1（mTORC1）的机制靶标信号的组成性激活会导致颅骨发育异常，尺寸减小，形状变圆。与颅底前后生长减少相反，突变小鼠还表现出颅底软骨症的显着扩展，包括蝶骨间软骨症（ISS）和蝶枕软骨症（SOS）。由于细胞数量和大小增加而细胞增殖没有改变，因此TSC1缺陷型小鼠的颅底软骨复合体扩张是静息区扩张的原因。此外，我们的数据显示，mTORC1活性在野生型小鼠的静息区和增殖区软骨细胞中受到抑制，和Tsc1缺失激活静息区软骨细胞的mTORC1信号传导。因此,TSC1缺陷小鼠静息区的软骨细胞获得了通常归因于肥大前软骨细胞的特征，包括高mTORC1活性，增加细胞大小，PTH1R（甲状旁腺激素1受体）和IHH（印度刺猬）的表达水平增加。最后,用雷帕霉素治疗，mTORC1的抑制剂，挽救了综合征的异常。我们的结果确立了TSC1-mTORC1信号传导在调节颅底骨发育中的重要作用，并表明在软骨复合体的静止区中的软骨细胞被维持在mTORC1抑制环境中。
