TGFβ Reprograms TNF Stimulation of Macrophages Towards a Non-canonical Pathway Driving Inflammatory Osteoclastogenesis

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jul 7

PMID 35798734

Authors

Yuhan Xia

Kazuki Inoue

Yong Du

Stacey J Baker

E Premkumar Reddy

Matthew B Greenblatt

Baohong Zhao

Affiliations

Soon will be listed here.

Abstract

It is well-established that receptor activator of NF-κB ligand (RANKL) is the inducer of physiological osteoclast differentiation. However, the specific drivers and mechanisms driving inflammatory osteoclast differentiation under pathological conditions remain obscure. This is especially true given that inflammatory cytokines such as tumor necrosis factor (TNF) demonstrate little to no ability to directly drive osteoclast differentiation. Here, we found that transforming growth factor β (TGFβ) priming enables TNF to effectively induce osteoclastogenesis, independently of the canonical RANKL pathway. Lack of TGFβ signaling in macrophages suppresses inflammatory, but not basal, osteoclastogenesis and bone resorption in vivo. Mechanistically, TGFβ priming reprograms the macrophage response to TNF by remodeling chromatin accessibility and histone modifications, and enables TNF to induce a previously unrecognized non-canonical osteoclastogenic program, which includes suppression of the TNF-induced IRF1-IFNβ-IFN-stimulated-gene axis, IRF8 degradation and B-Myb induction. These mechanisms are active in rheumatoid arthritis, in which TGFβ level is elevated and correlates with osteoclast activity. Our findings identify a TGFβ/TNF-driven inflammatory osteoclastogenic program, and may lead to development of selective treatments for inflammatory osteolysis.

Citing Articles

Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis.

Kiruba B, Naidu A, Sundararajan V, Lulu S S Heliyon. 2025; 11(1):e41342.

PMID: 39844998 PMC: 11751531. DOI: 10.1016/j.heliyon.2024.e41342.

Long non-coding RNA fine-tunes bone homeostasis and repair by orchestrating cellular crosstalk and β-catenin-OPG/Jagged1 pathway.

Qin Y, Shirakawa J, Xu C, Chen R, Yang X, Ng C Elife. 2024; 13.

PMID: 39714456 PMC: 11666238. DOI: 10.7554/eLife.98900.

Development of Zinc-Containing Chitosan/Gelatin Coatings with Immunomodulatory Effect for Soft Tissue Sealing around Dental Implants.

Han J, Sanders J, Andree L, van Oirschot B, Plachokova A, van den Beucken J Tissue Eng Regen Med. 2024; 22(1):57-75.

PMID: 39579168 PMC: 11711843. DOI: 10.1007/s13770-024-00680-y.

Histone demethylase JMJD1C advances macrophage foam cell formation and atherosclerosis progression by promoting the transcription of PCSK9.

Wang Y, Chen Y, Yang J, Sun W, Zhang X J Physiol Biochem. 2024; .

PMID: 39511107 DOI: 10.1007/s13105-024-01058-3.

The CD163/TWEAK/Fn14 axis: A potential therapeutic target for alleviating inflammatory bone loss.

Qian J, Ma Y, Huang X, Li X, Xu Y, Liu Z J Orthop Translat. 2024; 49:82-95.

PMID: 39430128 PMC: 11488420. DOI: 10.1016/j.jot.2024.09.002.

References

Skene P, Henikoff S . An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. Elife. 2017; 6. PMC: 5310842. DOI: 10.7554/eLife.21856. View

Brenner D, Blaser H, Mak T . Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol. 2015; 15(6):362-74. DOI: 10.1038/nri3834. View

Schett G, Gravallese E . Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012; 8(11):656-64. PMC: 4096779. DOI: 10.1038/nrrheum.2012.153. View

Heinz S, Benner C, Spann N, Bertolino E, Lin Y, Laslo P . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010; 38(4):576-89. PMC: 2898526. DOI: 10.1016/j.molcel.2010.05.004. View

Houde N, Chamoux E, Bisson M, Roux S . Transforming growth factor-beta1 (TGF-beta1) induces human osteoclast apoptosis by up-regulating Bim. J Biol Chem. 2009; 284(35):23397-404. PMC: 2749113. DOI: 10.1074/jbc.M109.019372. View

Miossec P, Naviliat M, Dupuy dAngeac A, Sany J, Banchereau J . Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthritis Rheum. 1990; 33(8):1180-7. DOI: 10.1002/art.1780330819. View

Park S, Kang K, Giannopoulou E, Qiao Y, Kang K, Kim G . Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat Immunol. 2017; 18(10):1104-1116. PMC: 5605457. DOI: 10.1038/ni.3818. View

Guo X, Wang X . Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 2008; 19(1):71-88. PMC: 3606489. DOI: 10.1038/cr.2008.302. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

10.

Choi Y, Arron J, Townsend M . Promising bone-related therapeutic targets for rheumatoid arthritis. Nat Rev Rheumatol. 2009; 5(10):543-8. PMC: 2797318. DOI: 10.1038/nrrheum.2009.175. View

11.

Sokhi U, Liber M, Frye L, Park S, Kang K, Pannellini T . Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models. Nat Commun. 2018; 9(1):658. PMC: 5811492. DOI: 10.1038/s41467-018-03081-7. View

12.

Quinn J, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N . Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Miner Res. 2001; 16(10):1787-94. DOI: 10.1359/jbmr.2001.16.10.1787. View

13.

Ciardiello D, Elez E, Tabernero J, Seoane J . Clinical development of therapies targeting TGFβ: current knowledge and future perspectives. Ann Oncol. 2020; 31(10):1336-1349. DOI: 10.1016/j.annonc.2020.07.009. View

14.

Aspenberg P . Denosumab and atypical femoral fractures. Acta Orthop. 2013; 85(1):1. PMC: 3940980. DOI: 10.3109/17453674.2013.859423. View

15.

Yasui T, Kadono Y, Nakamura M, Oshima Y, Matsumoto T, Masuda H . Regulation of RANKL-induced osteoclastogenesis by TGF-β through molecular interaction between Smad3 and Traf6. J Bone Miner Res. 2011; 26(7):1447-56. DOI: 10.1002/jbmr.357. View

16.

Morita M, Yoshida S, Iwasaki R, Yasui T, Sato Y, Kobayashi T . Smad4 is required to inhibit osteoclastogenesis and maintain bone mass. Sci Rep. 2016; 6:35221. PMC: 5059689. DOI: 10.1038/srep35221. View

17.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

18.

Wu M, Chen G, Li Y . TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016; 4:16009. PMC: 4985055. DOI: 10.1038/boneres.2016.9. View

19.

Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S . Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 2000; 191(2):275-86. PMC: 2195746. DOI: 10.1084/jem.191.2.275. View

20.

Gaarenstroom T, Hill C . TGF-β signaling to chromatin: how Smads regulate transcription during self-renewal and differentiation. Semin Cell Dev Biol. 2014; 32:107-18. DOI: 10.1016/j.semcdb.2014.01.009. View