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Critical Reviews™ in Immunology
IF: 1.352 5-Year IF: 3.347 SJR: 0.657 SNIP: 0.55 CiteScore™: 2.19

ISSN Print: 1040-8401
ISSN Online: 2162-6472

Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2018025874
pages 253-261

Does TNF Promote or Restrain Osteoclastogenesis and Inflammatory Bone Resorption?

Baohong Zhao
Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, and Department of Medicine, Weill Cornell Medical College, 535 E. 70th Street New York, New York 10021


Chronic inflammation is one of the most evident and common pathological conditions leading to deregulated osteoclastogenesis and bone remodeling. Tumor necrosis factor (TNF) as a pleiotropic cytokine plays a key role, not only in inflammation, but also in bone erosion in diseases associated with bone loss. TNF can stimulate the proliferation of osteoclast precursors and, in most conditions, act together with other cytokines and growth factors such as receptor activator of nuclear factor (NF)-[kappa]B ligand (RANKL), interleukin-6, and transforming growth factor beta to synergistically promote osteoclast formation and bone resorption in vivo. A longstanding enigma in the field is why TNF alone is not able to induce osteoclast differentiation as effectively as the same superfamily member RANKL, a physiological master osteoclastogenic cytokine. Recent studies have highlighted several lines of evidence showing the intrinsic mechanisms through RBP-J, NF-[kappa]B p100/TNF receptor-associated factor 3, or interferon regulatory factor-8 that restrain TNF-induced osteoclast differentiation and bone resorption. These feedback inhibitory mechanisms driven by TNF shed light into the current paradigm of osteoclastogenesis and would provide novel therapeutic implications on controlling inflammatory bone resorption.

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