Abstract
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.
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology
Cited by
8 articles.
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