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

ABSTRACT: Balanced osteoclast differentiation is crucial in maintaining skeleton health through life. Receptor activator of nuclear factor kappa-Β (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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152912 | GEO | 2021/03/25

REPOSITORIES: GEO

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Project description:Background Skeletal morbidity in cancer patients has a major impact on quality of life and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune-checkpoint inhibitors (ICI) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICI on bone turnover by longitudinal assessment of bone turnover markers (BTM) in cancer patients and by validation in a novel bioengineered 3D model of bone remodeling. Methods Serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-propeptide, PINP; and osteocalcin, OCN) were measured before each ICI application (PD1 inhibitors, PD1i or PD-L1 inhibitors, PD1i) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation upon treatment with ICI. In addition, their effect on bone remodeling was assessed by immunohistochemistry, immunofluorescence and proteomics analysis in a dynamic 3D model of the bone multicellular unit (BMU). Results The longitudinal assessment of BTM revealed a significant decrease in CTX levels after 3 weeks, followed by a return to baseline levels within 3 months. In contrast, serum levels of PINP and OCN gradually increased from baseline to the last postbaseline assessment. In vitro, ICI impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling, but not JNK, ERK and AKT; while lacking any direct effect on osteogenesis. However, using our novel bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity upon ICI treatment by demonstrating impaired OC maturation along with increased OB differentiation. Conclusion Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with the OB/OC coupling of bone turnover and may potentially exert a protective effect on bone by impairing the differentiation OCs and indirectly promoting osteogenesis.

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

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