Bone morphogenetic protein 2 (BMP-2) can induce the differentiation of mesenchymal stem cells (MSCs) into different osteocyte cells, including chondrocytes, adipocytes, and endothelial cells. While BMP-2 can effectively induce chondrogenic differentiation and inhibit osteogenic differentiation of MSCs, it can also initiate hypertrophic differentiation and endochondral ossification. Previous studies have shown that Notch1 plays a significant role during the early stages of chondrogenic lineage determination and that Notch1 signaling is crucial for the chondrogenic differentiation and endochondral ossification of MSCs.

In a recent study published in the Genes & Diseases journal, researchers at Chongqing Medical University, The University of Chicago Medical Center, and the Chinese Academy of Medical Sciences & Peking Union Medical College used both in vivo and in vitro MSC differentiation models to investigate the role and significance of Notch1 in regulating BMP2-induced chondrogenic differentiation and endochondral ossification.

The authors showed that BMP-2 stimulation induced chondrogenic differentiation of MSCs in the early stages, followed by osteogenic differentiation in the later stages. There was also a simultaneous increase in the expression of the Notch receptor in the early stages, and Notch1 and Jagged1 during the mid-to-late stages. BMP-2 further up-regulated the protein expression of NICD1 and RBPjk, suggesting that Notch1 signaling participates in BMP2-induced endochondral ossification of MSCs.

Furthermore, the down-regulation of Notch1 signaling i) promoted BMP2-induced chondrogenic differentiation of MSCs, as evident from the increased levels of the key chondrogenic differentiation transcription factor Sox9 and the chondrogenic differentiation marker Col2a1; ii) inhibited BMP2-induced osteogenic differentiation, which was associated with decreased levels of Runx2, Col1a1, and OPN; and iii) inhibited BMP2-induced blood vessels and trabecular bone formation. The up-regulation of Notch1 signaling exerted the opposite effect, however, highlighting its regulatory role in BMP2-induced endochondral ossification.

Mechanistically, activated Notch1 signaling promotes endochondral ossification by i) suppressing Sox9 expression via RBPjk-dependent Sox9 promoter inactivation, resulting in the inhibition of osteogenic differentiation and the promotion of chondrogenic differentiation; and ii) promoting VEGFA-mediated angiogenesis.

In conclusion, this study shows that Notch1 signaling regulates BMP2-induced osteogenic, chondrogenic, and angiogenic differentiation of MSCs. Furthermore, Notch1-mediated regulation of Sox9 determines the chondrogenic or osteogenic outcome in MSCs, highlighting its pivotal role in mediating the maintenance of BMP2-induced cartilage regeneration.

Reference

Title of the original paper: Notch1 signaling regulates Sox9 and VEGFA expression and governs BMP2-induced endochondral ossification of mesenchymal stem cells

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2024.101336

Funding Information:

The Science and Technology Research Program of the Chongqing Education Commission (China) (No. KJQN202100431, KJZD-M202100401).
The National Natural Science Foundation of China (No. 81972069, 82002312)
CQMU Program for Youth Innovation in Future Medicine (Chongqing, China) (No. W0154)
Innovation Project from Chongqing Municipal Education Commission (China) (No. CYB21169)
Cultivating Program and Candidate of Tip-Top Talent of The First Affiliated Hospital of Chongqing Medical University (Chongqing, China) (No. BJRC2021-04)
Cultivating Program of Postdoctoral Research of The First Affiliated Hospital of Chongqing Medical University (Chongqing, China) (No. CYYY-BSHPYXM-202202)
Chongqing Postdoctoral Research Program (Chongqing, China) (No. 2021XM1029)
China Postdoctoral Science Foundation (No. 2022M720605)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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