Journal Article

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

Liu, Xiaonan, Ferbeyre, Gerardo, Guo, Qiaoyue, Chai, Yu, Su, Weiping, Liu, Guanqiao, Gao, Peisong, Lv, Xiao, Yu, Bin, Cao, Xu, Wan, Mei

2021

Overview

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. Glucocorticoids (GCs) inhibit bone angiogenesis and affect bone development, but the underlying mechanisms remain unclear. Here, the authors show that GCs induce vascular cell senescence during bone development by inhibiting angiogenin secretion from osteoclasts, impairing angiogenesis via endothelial Plexin B2, resulting in unpaired bone growth.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/32 / 14/63 / 59/5 / 631/136/16 / 631/443/63 / 631/80/509 / 64 / 64/60 / Angiogenesis / Angiogenin / Animals / Apoptosis - drug effects / Biomedical materials / Blood vessels / Bone Development - drug effects / Bone growth / Cell Proliferation - drug effects / Cellular Senescence - drug effects / Cellular Senescence - genetics / Children / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Glucocorticoids / Glucocorticoids - pharmacology / Human Umbilical Vein Endothelial Cells / Humanities and Social Sciences / Humans / Immunohistochemistry / In Situ Hybridization, Fluorescence / Inflammation / Long bone / Metaphysis / Methylprednisolone - pharmacology / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / multidisciplinary / Neovascularization, Pathologic / Neovascularization, Physiologic - drug effects / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Osteoclasts / Osteoclasts - drug effects / Osteoclasts - enzymology / Osteoclasts - metabolism / Osteogenesis / Osteogenesis - drug effects / Recombinant Proteins / Ribonuclease, Pancreatic - genetics / Ribonuclease, Pancreatic - metabolism / Ribonuclease, Pancreatic - pharmacology / RNA, Ribosomal - biosynthesis / RNA, Small Interfering / rRNA / Science / Science (multidisciplinary) / Senescence / Signal Transduction - drug effects / Signal Transduction - genetics / Skeleton / Tomography Scanners, X-Ray Computed / Transcription