Fibronectin 1 activates WNT/β-catenin signaling to induce osteogenic differentiation via integrin β1 interaction

Abstract

Osteoporosis (OP) is a systemic skeletal disease leading to fragility fractures and is a major health issue globally. WNT/β-catenin signaling regulates bone-remodeling processes and plays vital roles in OP development. However, the underlying regulatory mechanisms behind WNT/β-catenin signaling in OP requires clarification, as further studies are required to identify novel alternate therapeutic agents to improve OP. Here we report that fibronectin 1 (FN-1) promoted differentiation and mineralization of osteoblasts by activating WNT/β-catenin pathway, in cultured pre-osteoblasts. With isobaric tags for relative and absolute quantitation labeling proteomics analysis, we investigated protein changes in bone samples from OP patients and normal controls. FN-1 accumulated in osteoblasts in bone samples from OP patients and age-related OP mice compared to control group. In addition, we observed that integrin β1 (ITGB1) acts as an indispensable signaling molecule for the interplay between FN-1 and β-catenin, and that FN-1 expression increased, but ITGB1 expression decreased in osteoblasts during OP progression. Therefore, our study reveals a novel explanation for WNT/β-catenin pathway inactivation in OP pathology. Supplying of FN-1 and ITGB1 may provide a potential therapeutic strategy in improving bone formation during OP.

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Fig. 1: FN-1 modulates osteogenic differentiation in vitro.
Fig. 2: FN-1 interacts with and promotes the nuclear translocation of β-catenin in osteoblasts.
Fig. 3: FN-1 expression in OP patient bone samples is significantly higher than the normal group.
Fig. 4: FN-1 expression accumulates in osteoblasts in aging mice.
Fig. 5: ITGB1 is essential for FN-1 in promoting osteogenesis via β-catenin signaling.

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Funding

This work was supported by the Guangxi Key R&D Project (Guike AB18050008), Guangxi Science and Technology Program (2018GXNSFAA294116, 2018GXNSFAA138074), High-level Innovation team and Outstanding Scholars Program of Colleges and Universities in Guangxi: innovative team of basic and Clinical Comprehensive Research on Bone and Joint degenerative Diseases, Scientific Research Project of High-level talents in the affiliated Hospital of Youjiang Medical College for nationalities (R20196301 and R20196306), and Open Project of Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases.

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YT, KL, and JL conceived the project, designed and supervised the experiments. KL and JL wrote the paper. CY, CW, and JZ performed the experiments and analyzed the data. QL, FH, and FL helped with the cell-cultured experiments and immunoblotting analysis. YL, JC, FZ, and CH helped prepare the figures and finished the IHC/IF analysis.

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Correspondence to Jia Liu or Kai Li or Yujin Tang.

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Yang, C., Wang, C., Zhou, J. et al. Fibronectin 1 activates WNT/β-catenin signaling to induce osteogenic differentiation via integrin β1 interaction. Lab Invest 100, 1494–1502 (2020). https://doi.org/10.1038/s41374-020-0451-2

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