Mapk7 deletion in chondrocytes causes vertebral defects by reducing MEF2C/PTEN/AKT signaling

Chengzhi Wu; Hengyu Liu; Dongmei Zhong; Xiaoming Yang; Zhiheng Liao; Yuyu Chen; Shun Zhang; Deying Su; Baolin Zhang; Chuan Li; Liru Tian; Caixia Xu; Peiqiang Su

doi:10.1016/j.gendis.2023.02.012

Mapk7 deletion in chondrocytes causes vertebral defects by reducing MEF2C/PTEN/AKT signaling

Genes Dis. 2023 Mar 24;11(2):964-977. doi: 10.1016/j.gendis.2023.02.012. eCollection 2024 Mar.

Authors

Chengzhi Wu¹, Hengyu Liu¹, Dongmei Zhong², Xiaoming Yang³, Zhiheng Liao¹, Yuyu Chen¹, Shun Zhang¹, Deying Su⁴, Baolin Zhang¹, Chuan Li⁵, Liru Tian⁵, Caixia Xu⁵, Peiqiang Su¹

Affiliations

¹ Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
² Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
³ Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
⁴ Guangdong Provincial Key Laboratory of Proteomics and State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
⁵ Research Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.

Abstract

Mutation of the MAPK7 gene was related to human scoliosis. Mapk7 regulated the development of limb bones and skulls in mice. However, the role of MAPK7 in vertebral development is still unclear. In this study, we constructed Col2a1-cre; Mapk7^f/f transgenic mouse model to delete Mapk7 in cartilage, which displayed kyphosis and osteopenia. Mechanistically, Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes, which impaired chondrocyte hypertrophy and attenuated vertebral ossification. In vivo, systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency. Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development, which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.

Keywords: Chondrocyte hypertrophy; Growth plate; Kyphosis; MAPK7; MEF2C; Osteopenia; PI3K/AKT; PTEN.