TNF is a homeostatic regulator of distinct epigenetically primed human osteoclast precursors

Ansalone, C., Cole, J., Chilaka, S., Sunzini, F., Sood, S., Robertson, J., Siebert, S. , McInnes, I. B. and Goodyear, C. (2021) TNF is a homeostatic regulator of distinct epigenetically primed human osteoclast precursors. Annals of the Rheumatic Diseases, 80(6), pp. 748-757. (doi: 10.1136/annrheumdis-2020-219262) (PMID:33692019) (PMCID:PMC8142443)

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Objectives: Circulating myeloid precursors are responsible for post-natal osteoclast (OC) differentiation and skeletal health, although the exact human precursors have not been defined. Enhanced osteoclastogenesis contributes to joint destruction in rheumatoid arthritis (RA) and tumour necrosis factor (TNF) is a well-known pro-osteoclastogenic factor. Herein, we investigated the interplay between receptor activator of nuclear factor kappa-Β ligand (RANK-L), indispensable for fusion of myeloid precursors and the normal development of OCs, and TNF in directing the differentiation of diverse pre-OC populations derived from human peripheral blood. Methods: Flow cytometric cell sorting and analysis was used to assess the potential of myeloid populations to differentiate into OCs. Transcriptomic, epigenetic analysis, receptor expression and inhibitor experiments were used to unravel RANK-L and TNF signalling hierarchy. Results: TNF can act as a critical homoeostatic regulator of CD14+ monocyte (MO) differentiation into OCs by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct previously unidentified CD14−CD16−CD11c+ myeloid pre-OC population was exempt from this negative regulation. In healthy CD14+ MOs, TNF drove epigenetic modification of the RANK promoter via a TNFR1-IKKβ-dependent pathway and halted osteoclastogenesis. In a subset of patients with RA, CD14+ MOs exhibited an altered epigenetic state that resulted in dysregulated TNF-mediated OC homoeostasis. Conclusions: These findings fundamentally re-define the relationship between RANK-L and TNF. Moreover, they have identified a novel pool of human circulating non-MO OC precursors that unlike MOs are epigenetically preconditioned to ignore TNF-mediated signalling. In RA, this epigenetic preconditioning occurs in the MO compartment providing a pathological consequence of failure of this pathway.

Item Type:Articles
Additional Information:The work was supported by European Commission Seventh Framework Programme and Marie Curie Actions (project Osteoimmune; FP7-PEO- PLE-2011-ITN-289150) with additional support by ARUK Centre of Excellence for the Pathogenesis of Rheumatoid Arthritis (RACE/♯20298). FS was supported by an ARTICULUM Fellowship.
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Sunzini, Miss Flavia and Cole, Mr John and Sood, Dr Shatakshi and Chilaka, Dr Sabarinadh and Robertson, Dr Jamie and Ansalone, Dr Cecilia and Siebert, Professor Stefan and Goodyear, Professor Carl
Authors: Ansalone, C., Cole, J., Chilaka, S., Sunzini, F., Sood, S., Robertson, J., Siebert, S., McInnes, I. B., and Goodyear, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Annals of the Rheumatic Diseases
Publisher:BMJ Publishing Group
ISSN (Online):1468-2060
Published Online:10 March 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Annals of the Rheumatic Diseases 80(6): 748-757
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
166744OSTEOIMMUNE: Unrevealing the Interactions between the Immune System and BoneCarl GoodyearEuropean Commission (EC)FP7 ITN 289150 OSTEOIII - Immunology
190682Rheumatoid Arthritis Centre of Excellence (RACE - Towards a Cure)Iain McInnesVersus Arthritis (ARTRESUK)MP20298III - Immunology