B-cell lymphoma 3-encoded protein (Bcl3) is an intimate and context-specific regulator of the NF-kB family of transcription factors, a ubiquitous master regulator involved in many homeostatic and inflammatory processes. NFkB signalling determines the fates of bone-forming osteoblasts and bone-resorbing osteoclasts. Herein we show that Bcl3 is a negative regulator of NFkB via control of osteoblast and osteoclast function. Mice lacking Bcl3 (Bcl3/) have congenitally increased bone density, long bone dwarfism, increased biomechanical strength and altered bone turnover. Bcl3/ osteoblasts and osteoclasts have accelerated differentiation and increased activity; whereas, rescue overexpression with a Bcl3 mimetic peptide inhibits differentiation. Early-differentiating Bcl3/ osteoblasts have altered gene transcription favouring bone formation, including perturbation of the RANKL-OPG axis. In a model of osteoarthritic aberrant mineralisation Bcl3/ mice exhibit decreased pathological osteophyte formation. Cumulatively, these findings identify Bcl3 as a viable target for controlling NFkB signalling in the treatment of skeletal pathologies. SOURCE: Hussain Jaffery (hussain.jaffery@glasgow.ac.uk) -  University of Glasgow

Pluto Bioinformatics

GSE125153: NF-kB regulator Bcl3 modulates bone density and turnover