Chondrocyte-Specific Knockout of TSC-1 Leads to Congenital Spinal Deformity in Mice.

Cheng Yang,Dadi Jin,Zhen Li,He Cao,Bo Yan,Xiaochun Bai,Yuhui Chen,Shicai Fan,Jiajun Tang,Rongping Zhou,Pinglin Lai,Bin Huang,Daozhang Cai,Keming Chen

doi:10.1155/2017/8215805

Abstract

Congenital spinal deformity is the most severe clinical orthopedic issue worldwide. Among all the pathological processes of congenital spinal deformity, the imbalance of endochondral ossification is considered to be the most important developmental cause of spinal dysplasia. We established chondrocyte-specific TSC-1 knockout (KO) mice to overactivate the energy metabolic component, mammalian target of rapamycin complex 1 (mTORC1), and measured the spinal development by general, imaging, histological, and Western-blot assessments. In addition to skeletal dysplasia, the KO mice displayed severe congenital spinal deformity and significant intervertebral disc changes. This study suggests that, in the process of endochondral ossification, excessive activation of mTORC1 signaling in chondrocytes induces obvious spinal deformity, and the chondrocytes may be the cell type responsible for congenital spinal deformity.

Highlights

Congenital spinal deformity is the most severe clinical orthopedic issue worldwide
No general alterations were observed between WT and KO mice at 1 and 7 days (Figures 1(a) and 1(b); p > 0.05), a significant reduction in body length and weight was seen in KO mice at 21 and 60 days when compared to WT mice (Figures 1(a) and 1(b); p < 0.001)
Hypertrophic chondrocytes and primary ossification center were observed in each intervertebral disc of KO mice, there was still a delay in spinal development (Figure 6). These results suggest that the congenital spinal deformity of chondrocyte-specific TSC-1 KO mice was derived from overactivation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling

Summary

Introduction

Congenital spinal deformity is the most severe clinical orthopedic issue worldwide. For spontaneous chest dysplasia and functional loss of respiratory organs, congenital spinal deformity is considered to be a fatal disorder with >60% mortality [1]. Due to the molecular mechanism involved, the pathological process of congenital spinal deformity is not fully understood. Endochondral ossification, a process in which bone formation initiates from a cartilage intermediate, is crucial for skeletal development [2, 3]. In this process, periodic activation of multiple signaling pathways plays a significant role and disturbance of these pathways leads to skeletal disorders like scoliosis and kyphosis [4,5,6,7,8,9]. Recent studies have shown that mammalian target of rapamycin (mTOR) plays a vital role in cartilage growth and skeletal development.

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