IĸB Protein BCL3 as a controller of osteogenesis and bone health

Jaffery, H. et al. (2023) IĸB Protein BCL3 as a controller of osteogenesis and bone health. Arthritis and Rheumatology, 75(12), 2148-2160-2148-2160. (doi: 10.1002/art.42639) (PMID:37410754)

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Objective IĸB protein B cell lymphoma 3-encoded protein (BCL3) is a regulator of the NF-κB family of transcription factors. NF-κB signaling 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. Methods To assess the contribution of BCL3 to skeletal homeostasis, neonatal mice (n = 6–14) lacking BCL3 (Bcl3−/−) and wild-type (WT) controls were characterized 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 destabilization of the medial meniscus model of osteoarthritic osteophytogenesis was used to understand adult bone formation in Bcl3−/− mice (n = 11–13). Results Evaluation of Bcl3−/− mice revealed congenitally increased bone density, long bone dwarfism, increased bone biomechanical strength, and altered bone turnover. Molecular and cellular characterization of mesenchymal precursors showed that Bcl3−/− cells displayed an accelerated osteogenic transcriptional profile that led 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 exhibited decreased pathological osteophyte formation (P < 0.05). Conclusion Cumulatively, these findings demonstrate that BCL3 controls developmental mineralization to enable appropriate bone formation, whereas in a pathological setting, it contributes to skeletal pathology.

Item Type:Articles
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Dunning, Mrs Lynette and Akbar, Mr Moeed and Cole, Mr John and Carmody, Dr Ruaidhri and Huesa, Dr Carmen and Chilaka, Dr Sabarinadh and Jaffery, Dr Hussain and Goodyear, Professor Carl and Doonan, Dr James and Tanner, Professor Kathleen
Authors: Jaffery, H., Huesa, C., Chilaka, S., Cole, J., Doonan, J., Akbar, M., Dunning, L., Tanner, K. E., van 't Hof, R. J., McInnes, I. B., Carmody, R. J., and Goodyear, C. S.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Arthritis and Rheumatology
ISSN (Online):2326-5205
Published Online:06 July 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Arthritis and Rheumatology 75(12):2148-2160
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
169637Molecular Functions in Disease (PhD Studentship 2012-2016)Carl GoodyearWellcome Trust (WELLCOTR)099786/Z/12/ZSII - Immunology & Infection
303229RACE RenewalIain McInnesVersus Arthritis (ARTRESUK)NW/22072SII - Immunology & Infection