TNF‐α has both stimulatory and inhibitory effects on mouse monocyte‐derived osteoclastogenesis

Abstract

Phenotypically different osteoclasts may be generated from different subsets of precursors. To what extent the formation of these osteoclasts is influenced or mediated by the inflammatory cytokine TNF‐α, is unknown and was investigated in this study. The osteoclast precursors early blasts (CD31hiLy‐6C−), myeloid blasts (CD31+Ly‐6C+), and monocytes (CD31−Ly‐6Chi) were sorted from mouse bone marrow using flow cytometry and cultured with M‐CSF and RANKL, with or without TNF‐α. Surprisingly, TNF‐α prevented the differentiation of TRAcP+ osteoclasts generated from monocytes on plastic; an effect not seen with early blasts and myeloid blasts. This inhibitory effect could not be prevented by other cytokines such as IL‐1β or IL‐6. When monocytes were pre‐cultured with M‐CSF and RANKL followed by exposure to TNF‐α, a stimulatory effect was found. TNF‐α also stimulated monocytes’ osteoclastogenesis when the cells were seeded on bone. Gene expression analysis showed that when TNF‐α was added to monocytes cultured on plastic, RANK, NFATc1, and TRAcP were significantly down‐regulated while TNF‐αR1 and TNF‐αR2 were up‐regulated. FACS analysis showed a decreased uptake of fluorescently labeled RANKL in monocyte cultures in the presence of TNF‐α, indicating an altered ratio of bound‐RANK/unbound‐RANK. Our findings suggest a diverse role of TNF‐α on monocytes’ osteoclastogenesis: it affects the RANK‐signaling pathway therefore inhibits osteoclastogenesis when added at the onset of monocyte culturing. This can be prevented when monocytes were pre‐cultured with M‐CSF and RANKL, which ensures the binding of RANKL to RANK. This could be a mechanism to prevent unfavorable monocyte‐derived osteoclast formation away from the bone.

Polymorphisms in theSP110andTNF-αGene and Susceptibility to Pulmonary and Spinal Tuberculosis among Southern Chinese Population

“…Although the above two genetic models showed that the upper bound of 95% CI exceeded 1 (1.053) or closed to 1 (0.999), the presence of the -238 A allele was considered a trend to decrease the risk of STB. The regulatory role of TNF- α in the differentiation of osteoclast might be related to this [ 34 ]. However, we failed to find any association of TNF-α -308G>A polymorphism with PTB and STB in our study populations.…”

The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK

“…However, LPS is only a relevant stimulus in septic bone diseases, whereas most osteoclast-associated conditions, including a plethora of arthritis, involve sterile inflammatory conditions in which S100A8/A9 is strongly increased. Other factors that have been described to inhibit precursor-to-osteoclast differentiation are IL-1b and TNF-a (41,42). Together, these studies suggest that the timing of exposure to proinflammatory factors like S100A8/A9 in the course of osteoclast differentiation might act as a switch to determine the osteoclast fate.…”

“…Together, these data indicate that the S100A9 effects are directly affecting the RANK expression levels rather than indirectly via decreased expression of the M-CSF receptor. Interestingly, we showed that both IL-1b and TNF-a secretion were increased after exposure to S100A9, which has been shown to reduce osteoclast differentiation from precursors (41,42). However, after exposure to S100A9, addition of IL-1RA to block IL-1 did not rescue the membrane expression of RANK.…”

The Osteocyte as a Novel Key Player in Understanding Periodontitis Through its Expression of RANKL and Sclerostin: a Review

“…Together, this inflammatory scene within the soft connective tissue of the periodontium sets the stage for activation of osteoclast precursors, where inflammatory cytokines such as IL-1β [ 14 ] and TNF-α [ 15 ] will enhance osteoclast formation and activity. However, this view does not take into account the recent appraisal of the osteocyte as a major RANKL producing cell [ 16 , 17 ].…”