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Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways.
J Biol Chem. 2001 Jan 05; 276(1):563-8.JB

Abstract

Tumor necrosis factor-alpha (TNF) and the ligand for receptor activator of NF-kappaB (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 precursors 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 I kappa B/NF-kappa B, ERKs, and cJun/AP-1. Consistent with impaired osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of I kappa B, NF-kappa B, 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.

Authors+Show Affiliations

Department of Orthopaedic Research, Barnes-Jewish Hospital at Washington University School of Medicine, St. Louis, Missouri 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11032840

Citation

Zhang, Y H., et al. "Tumor Necrosis Factor-alpha (TNF) Stimulates RANKL-induced Osteoclastogenesis Via Coupling of TNF Type 1 Receptor and RANK Signaling Pathways." The Journal of Biological Chemistry, vol. 276, no. 1, 2001, pp. 563-8.
Zhang YH, Heulsmann A, Tondravi MM, et al. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem. 2001;276(1):563-8.
Zhang, Y. H., Heulsmann, A., Tondravi, M. M., Mukherjee, A., & Abu-Amer, Y. (2001). Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. The Journal of Biological Chemistry, 276(1), 563-8.
Zhang YH, et al. Tumor Necrosis Factor-alpha (TNF) Stimulates RANKL-induced Osteoclastogenesis Via Coupling of TNF Type 1 Receptor and RANK Signaling Pathways. J Biol Chem. 2001 Jan 5;276(1):563-8. PubMed PMID: 11032840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. AU - Zhang,Y H, AU - Heulsmann,A, AU - Tondravi,M M, AU - Mukherjee,A, AU - Abu-Amer,Y, PY - 2000/10/18/pubmed PY - 2001/3/3/medline PY - 2000/10/18/entrez SP - 563 EP - 8 JF - The Journal of biological chemistry JO - J Biol Chem VL - 276 IS - 1 N2 - Tumor necrosis factor-alpha (TNF) and the ligand for receptor activator of NF-kappaB (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 precursors 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 I kappa B/NF-kappa B, ERKs, and cJun/AP-1. Consistent with impaired osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of I kappa B, NF-kappa B, 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11032840/Tumor_necrosis_factor_alpha__TNF__stimulates_RANKL_induced_osteoclastogenesis_via_coupling_of_TNF_type_1_receptor_and_RANK_signaling_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(18)44273-1 DB - PRIME DP - Unbound Medicine ER -