Chondrocyte Tsc1 controls cranial base bone development by restraining the premature differentiation of synchondroses.
Chondrocyte Tsc1 controls cranial base bone development by restraining the premature differentiation of synchondroses.
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DOI：
10.1016/j.bone.2021.116142
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发表时间：
2021-12
期刊：
影响因子：
4.1
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Hsieh YL;Wei X;Wang Y;Zhang H;Qi S;Xie D;Mishina Y;Mendonça D;Hatch N;Liu F
颅底骨是通过软骨内骨化形成的。软骨结合是位于颅底骨之间的生长板，有助于颅骨的前后生长。颅底软骨结合中软骨细胞的协调增殖和分化对颅底骨的生长至关重要。在此，我们报告，组成性激活的机制目标的雷帕霉素复合物1（mTORC 1）信号通过Tsc 1（多发性硬化症1）缺失软骨细胞导致颅骨发育异常的大小和圆形。与颅底前后生长减少相反，突变小鼠还表现出颅底软骨结合的显著扩张，包括蝶骨间软骨结合（ISS）和蝶枕软骨结合（SOS）。TSC 1缺陷小鼠的颅底软骨结合扩张是由于静止区的扩张，这是由于细胞数量和大小增加而细胞增殖没有改变。此外，我们的数据表明，mTORC 1活性抑制在休息区和增殖区软骨细胞的野生型小鼠，和Tsc 1缺失激活mTORC 1信号的软骨细胞在休息区区域。因此，TSC 1缺陷型小鼠的静止区中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mTORC 1活性、增大的细胞尺寸以及增加的PTH 1 R（甲状旁腺激素1受体）和IHH（印度刺猬）表达水平。最后，用mTORC 1抑制剂雷帕霉素治疗，挽救了软骨结合的异常。我们的研究结果确立了TSC 1-mTORC 1信号在调节颅底骨发育中的重要作用，并表明软骨结合静止区的软骨细胞维持在mTORC 1抑制环境中。
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 expansion in 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.
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