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NF-κB Signaling Negatively Regulates Osteoblast Dedifferentiation during Zebrafish Bone Regeneration
Rashmi Mishra1, Ivonne Sehring1, Maria Cederlund1
1Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Abstract:
Dedifferentiation of mature cells is an intriguing cellular process associated with regeneration of several organs. During zebrafish fin regeneration, osteoblasts dedifferentiate to osteogenic progenitors that provide source cells for bone restoration. We performed a high-content in vivo chemical screen for regulators of osteoblast dedifferentiation and fin regenerative growth. NF-κB signaling emerged as a specific regulator of dedifferentiation. The pathway is active in mature osteoblasts and downregulated prior to dedifferentiation. Pathway activation blocked osteoblast dedifferentiation, while NF-κB signaling inhibition enhanced dedifferentiation. Conditional Cre-lox-mediated NF-κB signaling manipulation specifically in osteoblasts showed that the pathway acts cell autonomously to interfere with osteoblast dedifferentiation. NF-κB signaling acts upstream of retinoic acid (RA) signaling, which also needs to be downregulated for dedifferentiation to occur, via suppression of the RA-degrading enzyme cyp26b1. Our findings shed light on the molecular regulation of regenerative cellular plasticity.
Insights
Nuclear factor-kappa B (NF-κB) signaling inhibits osteoblast dedifferentiation during zebrafish fin regeneration. Inhibiting this pathway promotes dedifferentiation, revealing a key mechanism in cellular plasticity and bone repair.
Area of Science:
- Cell Biology
- Regenerative Medicine
- Molecular Biology
Background:
- Cellular dedifferentiation is crucial for organ regeneration, including bone restoration.
- In zebrafish fin regeneration, mature osteoblasts dedifferentiate into progenitors.
Purpose of the Study:
- To identify regulators of osteoblast dedifferentiation and fin regeneration.
- To elucidate the molecular mechanisms controlling cellular plasticity during regeneration.
Main Methods:
- High-content in vivo chemical screen for dedifferentiation regulators.
- NF-κB signaling pathway manipulation in osteoblasts (chemical and genetic).
- Analysis of retinoic acid (RA) signaling and cyp26b1 expression.
Main Results:
- NF-κB signaling specifically regulates osteoblast dedifferentiation.
- NF-κB pathway activation blocks dedifferentiation; inhibition enhances it.
- NF-κB acts cell-autonomously and upstream of RA signaling by suppressing cyp26b1.
Conclusions:
- NF-κB signaling is a critical negative regulator of osteoblast dedifferentiation.
- Downregulation of NF-κB and RA signaling is essential for regenerative cellular plasticity.
- Findings provide insights into molecular control of bone regeneration.
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