TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors
| Autor: | John J. Cole, C Ansalone, Sabarinadh Chilaka, Jamie Robertson, Flavia Sunzini, Stefan Siebert, Iain B. McInnes, Carl S. Goodyear, Shatakshi Sood |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Myeloid Receptor expression Immunology Population Osteoclasts Rheumatoid Arthritis General Biochemistry Genetics and Molecular Biology Arthritis Rheumatoid 03 medical and health sciences 0302 clinical medicine Rheumatology Osteoclast Osteogenesis medicine Immunology and Allergy Homeostasis Humans Epigenetics Receptor education 030203 arthritis & rheumatology education.field_of_study business.industry Tumor Necrosis Factor-alpha Monocyte RANK Ligand tumour necrosis factors Cell Differentiation cytokines 030104 developmental biology medicine.anatomical_structure arthritis Cancer research Tumor necrosis factor alpha business |
| Zdroj: | Annals of the Rheumatic Diseases |
| ISSN: | 1468-2060 0003-4967 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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