NF-kB regulator Bcl3 modulates bone density and turnover

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. NF-kB signalling determines the fates of bone-forming osteoblasts and bone-resorbing osteoclasts. Herein we show that Bcl3 is a negative regulator of NF-kB 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 NF-kB signalling in the treatment of skeletal pathologies. Overall design: The study comprises a total of 12 tested samples - forming 4 groups with 3 biological replicates in each group. The experimental groups, namely Bcl3-/- (Bcl3 knockout), and the control groups, namely WT (wild-type), differ in genotype. Each genotype has two tested time-points - at Day 1 and Day 3 post-treatment. Thus, 3 replicates each for the following groups are submitted: Day 1 WT, Day 1 Bcl3-/-, Day 3 WT, and Day 3 Bcl3-/-.