β-catenin inhibition disrupts the homeostasis of osteogenic/adipogenic differentiation leading to the development of glucocorticoid-induced osteonecrosis of femoral head

Author:

Xia ChenjieORCID,Xu Huihui,Fang Liang,Chen Jiali,Yuan Wenhua,Fu Danqing,Wang Xucheng,He Bangjian,Xiao Luwei,Wu Chengliang,Tong Peijian,Chen DiORCID,Wang Pinger,Jin HongtingORCID

Abstract

AbstractGlucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased β-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting β-catenin signaling in glucocorticoid-induced GONFH rats. Col2+lineage largely contributes to BMSCs, and was found an osteogenic commitment in the femoral head through 9 months of lineage trace. Specific deletion ofβ-cateninin Col2+cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that β-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH, and identify an ideal genetic modified mouse model of GONFH.

Publisher

Cold Spring Harbor Laboratory

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