TNF is a homeostatic regulator of distinct epigenetically primed human osteoclast precursors
Balanced osteoclast differentiation is crucial in maintaining skeleton health through life. Receptor activator of nuclear factor kappa-? (RANK) is indispensable for OCs normal development in vivo and for the in vitro fusion of circulating progenitor cells into OCs. Many cytokines enhance RANK and RANK-ligand (RANK-L)-mediated differentiation of myeloid cells into OCs. In particular, tumor necrosis factor (TNF) is recognized as a potent activator and is associated with in vivo bone destruction in the context of OC dysregulation in inflammatory arthritis.  Paradoxically, infiltration of monocytes into TNF rich inflammatory sites does not lead to a preponderance of osteoclasts but rather macrophages. Recent in vivo murine studies have shown how circulating myeloid precursors play a crucial role in post-natal OC differentiation and skeletal health. However, little is known about such pathways in humans. Herein we demonstrate that, unexpectedly TNF can act as a critical homeostatic regulator of human CD14+ monocyte differentiation into osteoclast by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct, previously unidentified human CD11c+ myeloid pre-osteoclast population is exempt from this negative regulation. In healthy humans, to control cell fate and specifically overcome OC differentiation, TNF drives epigenetic modification of the RANK promoter via a TNFR1-IKK?-dependent pathway. In contrast in rheumatoid arthritis, patient-derived monocytes exhibit an altered epigenetic state that results in dysregulated TNF-mediated osteoclast homeostasis providing a pathologic consequence of failure of this pathway. Overall design: Examination of H3K4me3 in human monocytes from patients with and without rheumatoid arthritis