IĸB Protein BCL3 as a Controller of Osteogenesis and Bone Health

Abstract

ObjectiveIĸB protein B‐cell lymphoma 3‐encoded protein (BCL3) is a regulator of the NF‐κB family of transcription factors. NF‐κB signalling fundamentally influences the fate of bone‐forming osteoblasts and bone‐resorbing osteoclasts, but the role of BCL3 in bone biology has not been investigated. The objective of this study was to evaluate BCL3 in skeletal development, maintenance and osteoarthritic pathology.MethodsTo assess the contribution of BCL3 to skeletal homeostasis, neonatal mice (n = 6‐14) lacking BCL3 (Bcl3−/−) and WT controls were characterised for bone phenotype and density. To reveal the contribution to bone phenotype by the osteoblast compartment in Bcl3−/− mice, transcriptomic analysis of early osteogenic differentiation and cellular function (n = 3‐7) were assessed. Osteoclast differentiation and function in Bcl3−/− mice (n = 3‐5) was assessed. Adult 20‐week Bcl3−/− and WT mice bone phenotype, strength and turnover were assessed. A destabilisation of the medial meniscus (DMM) model of osteoarthritic ostephytogenesis was utilised to understand adult bone formation in Bcl3−/− mice (n = 11‐13).ResultsEvaluation of Bcl3−/− mice revealed congenitally increased bone density, long bone dwarfism, increased bone biomechanical strength and altered bone turnover. Molecular and cellular characterisation of mesenchymal precursors showed that Bcl3−/− cells display an accelerated osteogenic transcriptional profile that leads to enhanced differentiation into osteoblasts with increased functional activity; which could be reversed with a mimetic peptide. In a model of osteoarthritis‐induced osteophytogenesis, Bcl3−/− mice exhibit decreased pathological osteophyte formation (P < 0.05).ConclusionCumulatively, these findings demonstrate that BCL3 controls developmental mineralisation to enable appropriate bone formation, whilst in a pathological setting it contributes to skeletal pathology.image

Bone-Targeted Supramolecular Nanoagonist Assembled by Accurate Ratiometric Herbal-Derived Therapeutics for Osteoporosis Reversal

“…The top 20 related signal pathways were identified, among which the PPAR signaling pathway and NF-κB pathway were considered to play key roles in the augmentation of osteogenesis (Figure S6D). 60,61 ■ PHARMACOKINETIC PROFILE AND BIODISTRIBUTION Next, we turned to investigate the in vivo fate of carrier-free herbal-derived NAs after systemic administration to uncover the merits of self-delivery systems. The plasma drug concentration versus injection time profiles after intravenous injection of CGA, BER and NAs to C57BL/6J mice were illustrated in Figure 4A, and the pharmacokinetic parameters were listed in Table S1.…”

“…The top 20 related signal pathways were identified, among which the PPAR signaling pathway and NF-κB pathway were considered to play key roles in the augmentation of osteogenesis (Figure S6D). , …”