Estrogen-mediated downregulation of HIF-1 alpha signaling in B lymphocytes influences postmenopausal bone loss

Meng X, Lin Z, Cao S, Janowska I, Sonomoto K, Andreev D, Knab K, Wen J, Knaup K, Krönke G, Rizzi M, Schett G, Bozec A, Wiesener M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Bone Research Elsevier

Book Volume: 10

Journal Issue: 1

DOI: 10.1038/s41413-022-00189-x

Abstract

In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and high-throughput analyses, we demonstrate that prolonged HIF-1 alpha signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1 alpha in B cells prevents estrogen deficiency-induced bone loss in mice. Mechanistically, estrogen controls HIF-1 alpha protein stabilization through HSP70-mediated degradation in bone marrow B cells. The stabilization of HIF-1 alpha protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis. Induction of HSP70 expression by geranylgeranylacetone (GGA) administration alleviates ovariectomy-induced osteoporosis. Moreover, RANKL gene expression has a positive correlation with HIF1A expression in human B cells. In conclusion, HIF-1 alpha signaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1 alpha axis may serve as a new therapeutic target for osteoporosis.

Authors with CRIS profile

Xianyi Meng Juniorprofessur für Osteoimmunologie Zhen Lin Professur für Experimentelle Immuntherapie Shan Cao Juniorprofessur für Osteoimmunologie Darja Andreev Department of Medicine 3 – Rheumatology and Immunology Katharina Knab Department of Medicine 3 – Rheumatology and Immunology Jinming Wen Department of Medicine 3 – Rheumatology and Immunology Karl Knaup Department of Medicine 4 – Nephrology and Hypertension Gerhard Krönke Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Aline Bozec Juniorprofessur für Osteoimmunologie Michael Wiesener Professur für Innere Medizin (Nephrologie)

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A077: HIF pathway activation in B cells regulates postmenopausal bone loss Dec. 16, 2020 - Dec. 15, 2023

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE)

How to cite

APA:

Meng, X., Lin, Z., Cao, S., Janowska, I., Sonomoto, K., Andreev, D.,... Wiesener, M. (2022). Estrogen-mediated downregulation of HIF-1 alpha signaling in B lymphocytes influences postmenopausal bone loss. Bone Research, 10(1). https://doi.org/10.1038/s41413-022-00189-x

MLA:

Meng, Xianyi, et al. "Estrogen-mediated downregulation of HIF-1 alpha signaling in B lymphocytes influences postmenopausal bone loss." Bone Research 10.1 (2022).

BibTeX: Download