Tumor necrosis factor-α (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways

Yan Hong Zhang, Antoinette Heulsmann, M. Mehrdad Tondravi, Aditi Mukherjee, Yousef Abu-Amer

Research output: Contribution to journalArticle

378 Scopus citations

Abstract

Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust osteoclastogenesis by osteoclast precursots pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.

Original languageEnglish
Pages (from-to)563-568
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number1
DOIs
StatePublished - Jan 5 2001

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