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

Xianyi Meng; Zhen Lin; Shan Cao; Iga Janowska; Koshiro Sonomoto; Darja Andreev; Knab Katharina; Jinming Wen; Karl Xaver Knaup; Michael Sean Wiesener; Gerhard Krönke; Marta Rizzi; Georg Schett; Aline Bozec

doi:10.1038/s41413-022-00189-x

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

Bone Res. 2022 Feb 17;10(1):15. doi: 10.1038/s41413-022-00189-x.

Authors

Xianyi Meng^{1

2}, Zhen Lin^{1

2}, Shan Cao^{1

2}, Iga Janowska³, Koshiro Sonomoto^{1

2}, Darja Andreev^{1

2}, Knab Katharina^{1

2}, Jinming Wen^{1

2}, Karl Xaver Knaup⁴, Michael Sean Wiesener⁴, Gerhard Krönke^{1

2}, Marta Rizzi³, Georg Schett^{1

2}, Aline Bozec^{5

6}

Affiliations

¹ Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, 91054, Germany.
² Deutsches Zentrum fur Immuntherapie (DYI), Erlangen, 91054, Germany.
³ Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, 79106, Germany.
⁴ Department of Internal Medicine 4, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, 91054, Germany.
⁵ Department of Internal Medicine 3, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, 91054, Germany. aline.bozec@uk-erlangen.de.
⁶ Deutsches Zentrum fur Immuntherapie (DYI), Erlangen, 91054, Germany. aline.bozec@uk-erlangen.de.

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-1α signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1α in B cells prevents estrogen deficiency-induced bone loss in mice. Mechanistically, estrogen controls HIF-1α protein stabilization through HSP70-mediated degradation in bone marrow B cells. The stabilization of HIF-1α 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-1α signaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1α axis may serve as a new therapeutic target for osteoporosis.