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Published on: September 16, 2020
Mesenchymal stem cell-derived exosome NR4A2 inhibits fracture healing in aged rat by blocking NELL2-mediated
Peng Ye1, Rui Bai1, Xiaoli Ding1
1Second Orthopedic Trauma Ward, General Hospital of Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan 750004, China.
Abstract:
As a transcription factor, nuclear receptor subfamily 4 group A member 2 (NR4A2) regulates target gene transcription by directly binding to response elements within gene promoters. However, the exact role and molecular mechanism of NR4A2 in fracture healing have not been fully elucidated. Here, we identified NR4A2 as a key functional molecular cargo enriched in exosomes secreted by aged bone marrow stromal cells (BMSCs). Upon uptake by recipient cells, exosomal NR4A2 functioned as a transcriptional repressor that specifically bound to the promoter region of the Neural EGFL-like 2 (NELL2) gene, thereby suppressing its transcription. We further demonstrated that NELL2 acted as a critical adaptor protein that enhanced the binding affinity between fibronectin 1 (Fn1) and integrin β1, thereby licensing FAK/AKT cascade activation essential for osteogenic differentiation. Mechanistically, NR4A2-mediated suppression of NELL2 impaired the assembly of the NELL2/Fn1/integrin β1 complex and attenuated FAK/AKT phosphorylation, thereby inhibiting osteogenesis and culminating in delayed fracture healing. Collectively, our findings delineate a novel exosome-dependent regulatory axis, through which aged BMSCs deteriorated the bone repair microenvironment via the NR4A2/NELL2/FAK-AKT signaling cascade. This study reveals a previously unrecognized molecular mechanism underlying age-associated fracture healing impairment.
Insights
Aged bone marrow stromal cells (BMSCs) impair fracture healing by secreting exosomes containing nuclear receptor subfamily 4 group A member 2 (NR4A2). This molecule suppresses Neural EGFL-like 2 (NELL2) and hinders osteogenic differentiation via the FAK/AKT pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Regenerative Medicine
Background:
- Nuclear receptor subfamily 4 group A member 2 (NR4A2) is a transcription factor, but its role in fracture healing is unclear.
- Exosomes mediate intercellular communication, potentially influencing age-related decline in tissue repair.
Purpose of the Study:
- To elucidate the role and molecular mechanism of NR4A2 in fracture healing.
- To investigate the function of exosomal NR4A2 derived from aged bone marrow stromal cells (BMSCs).
Main Methods:
- Identification of NR4A2 in exosomes from aged BMSCs.
- Analysis of NR4A2 binding to the Neural EGFL-like 2 (NELL2) gene promoter.
- Assessment of NELL2's role in fibronectin 1 (Fn1)/integrin β1 complex formation and FAK/AKT signaling.
- Evaluation of osteogenic differentiation and fracture healing in response to NR4A2 modulation.
Main Results:
- NR4A2 was identified as a key cargo in exosomes from aged BMSCs.
- Exosomal NR4A2 suppressed NELL2 transcription by binding to its promoter.
- NELL2 deficiency impaired NELL2/Fn1/integrin β1 complex formation and FAK/AKT activation.
- NR4A2-mediated NELL2 suppression inhibited osteogenesis and delayed fracture healing.
Conclusions:
- Aged BMSCs impair fracture healing through exosomal NR4A2.
- The NR4A2/NELL2/FAK-AKT signaling axis is a novel mechanism for age-associated bone repair deficits.
- Targeting this pathway may offer therapeutic strategies for improving fracture healing in the elderly.
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