Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis

Xiaonan Liu, Yu Chai, Guanqiao Liu, Weiping Su, Qiaoyue Guo, Xiao Lv, Peisong Gao, Bin Yu, Gerardo Ferbeyre, Xu Cao and Mei Wan ()
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Xiaonan Liu: The Johns Hopkins University School of Medicine
Yu Chai: The Johns Hopkins University School of Medicine
Guanqiao Liu: The Johns Hopkins University School of Medicine
Weiping Su: The Johns Hopkins University School of Medicine
Qiaoyue Guo: The Johns Hopkins University School of Medicine
Xiao Lv: The Johns Hopkins University School of Medicine
Peisong Gao: Johns Hopkins University School of Medicine
Bin Yu: Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Gerardo Ferbeyre: Université de Montréal
Xu Cao: The Johns Hopkins University School of Medicine
Mei Wan: The Johns Hopkins University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Synthetic glucocorticoids (GCs), one of the most effective treatments for chronic inflammatory and autoimmune conditions in children, have adverse effects on the growing skeleton. GCs inhibit angiogenesis in growing bone, but the underlying mechanisms remain unclear. Here, we show that GC treatment in young mice induces vascular endothelial cell senescence in metaphysis of long bone, and that inhibition of endothelial cell senescence improves GC-impaired bone angiogenesis with coupled osteogenesis. We identify angiogenin (ANG), a ribonuclease with pro-angiogenic activity, secreted by osteoclasts as a key factor for protecting the neighboring vascular cells against senescence. ANG maintains the proliferative activity of endothelial cells through plexin-B2 (PLXNB2)-mediated transcription of ribosomal RNA (rRNA). GC treatment inhibits ANG production by suppressing osteoclast formation in metaphysis, resulting in impaired endothelial cell rRNA transcription and subsequent cellular senescence. These findings reveal the role of metaphyseal blood vessel senescence in mediating the action of GCs on growing skeleton and establish the ANG/PLXNB2 axis as a molecular basis for the osteoclast-vascular interplay in skeletal angiogenesis.

Date: 2021
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DOI: 10.1038/s41467-021-22131-1

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