TY - JOUR
T1 - TGFβ reprograms TNF stimulation of macrophages towards a non-canonical pathway driving inflammatory osteoclastogenesis
AU - Xia, Yuhan
AU - Inoue, Kazuki
AU - Du, Yong
AU - Baker, Stacey J.
AU - Premkumar Reddy, E.
AU - Greenblatt, Matthew B.
AU - Zhao, Baohong
N1 - Funding Information:
We thank Weill Cornell Medicine Genomics Core Facilities for next-generation sequencing, Dr. Franck Barrat for sharing the de-identified human CD14(+) monocytes isolated from the buffy coats purchased from New York Blood Center, Drs. Theresa Lu, Marie Dominique Ah Kioon, Vidyanath Chaudhary, Ruoxi Yuan, Chao Yang, Upneet Sokhi, Mahesh Bachu, Caroline Brauner, and Bikash Mishra for technical assistance, and Courtney Ng for critical review of the manuscript. We are grateful to the lab members from Dr. Baohong Zhao’s laboratory for their helpful discussions and assistance. M.B.G. holds a Career Award for Medical Scientists from the Burroughs Welcome Foundation, and a Pershing Square Sohn Prize for Young Investigators in Cancer Research. This work was supported by grants from the National Institutes of Health (AR075585 to MBG, AR068970, AR071463, and AR078212 to B.Z.) and by support for the Rosensweig Genomics Center at the Hospital for Special Surgery from The Tow Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding Information:
We thank Weill Cornell Medicine Genomics Core Facilities for next-generation sequencing, Dr. Franck Barrat for sharing the de-identified human CD14(+) monocytes isolated from the buffy coats purchased from New York Blood Center, Drs. Theresa Lu, Marie Dominique Ah Kioon, Vidyanath Chaudhary, Ruoxi Yuan, Chao Yang, Upneet Sokhi, Mahesh Bachu, Caroline Brauner, and Bikash Mishra for technical assistance, and Courtney Ng for critical review of the manuscript. We are grateful to the lab members from Dr. Baohong Zhao’s laboratory for their helpful discussions and assistance. M.B.G. holds a Career Award for Medical Scientists from the Burroughs Welcome Foundation, and a Pershing Square Sohn Prize for Young Investigators in Cancer Research. This work was supported by grants from the National Institutes of Health (AR075585 to MBG, AR068970, AR071463, and AR078212 to B.Z.) and by support for the Rosensweig Genomics Center at the Hospital for Special Surgery from The Tow Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85133641834&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31475-1
DO - 10.1038/s41467-022-31475-1
M3 - Article
C2 - 35798734
AN - SCOPUS:85133641834
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3920
ER -