NF-κB Signaling Negatively Regulates Osteoblast Dedifferentiation during Zebrafish Bone Regeneration

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.

Keywords: NF-kappaB; bglap; bone; dedifferentiation; fin; osteoblast; osteocalcin; plasticity; regeneration; zebrafish.