YBX1 Promotes Type H Vessel-dependent Bone Formation in an M5C-dependent Manner

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2024 Feb 22

PMID 38385749

Authors

Yu-Jue Li

Qi Guo

Ming-Sheng Ye

Guangping Cai

Wen-Feng Xiao

Sheng Deng

Ye Xiao

Affiliations

Soon will be listed here.

Abstract

RNA-binding proteins (RBPs) interact with RNA and ubiquitously regulate RNA transcripts during their life cycle, playing a fundamental role in the progression of angiogenesis-related diseases. In the skeletal system, endothelium-dependent angiogenesis is indispensable for bone formation. However, the role of RBPs in endothelium-dependent bone formation is unclear. Here, we show that RBP-Y-box-binding protein 1 (YBX1) was strongly reduced in the bone vasculature of ovariectomy (OVX) mice. Endothelial cell-specific deletion of Ybx1 impaired CD31-high, endomucin-high (CD31hiEMCNhi) endothelium morphology and resulted in low bone mass whereas Ybx1 overexpression promoted angiogenesis-dependent osteogenesis and ameliorated bone loss. Mechanistically, YBX1 deletion disrupted CD31, EMCN, and bone morphogenetic protein 4 (BMP4) stability in an m5C-dependent manner and blocked endothelium-derived BMP4 release, thereby inhibiting osteogenic differentiation of bone mesenchymal stromal cells. Administration of recombinant BMP4 protein restored impaired bone formation in Ybx1 deletion mice. Tail vein injection of CD31-modified polyethylene glycol-poly (lactic-co-glycolic acid) carrying sciadopitysin, a natural YBX1 agonist, pharmacologically partially reversed CD31hiEMCNhi vessels' decline and improved bone mass in both OVX and aging animals. These findings demonstrated the role of RBP-YBX1 in angiogenesis-dependent bone formation and provided a therapeutic approach for ameliorating osteoporosis.

Citing Articles

The Role of mRNA Modifications in Bone Diseases.

Li Z, Meng K, Lan S, Ren Z, Lai Z, Ao X Int J Biol Sci. 2025; 21(3):1065-1080.

PMID: 39897026 PMC: 11781163. DOI: 10.7150/ijbs.104460.

MLLT3 Regulates Melanoma Stemness and Progression by Inhibiting HMGB1 Nuclear Entry and MAGEA1 MC Modification.

Li Y, Liu H, Li J, Fu C, Jiang B, Chen B Adv Sci (Weinh). 2024; 12(10):e2408529.

PMID: 39716999 PMC: 11904942. DOI: 10.1002/advs.202408529.

Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications.

Balamurli G, Liew A, Tee W, Pervaiz S Redox Biol. 2024; 78:103441.

PMID: 39612910 PMC: 11629570. DOI: 10.1016/j.redox.2024.103441.

NSUN2 methylates IRF4 to affect the capacity of macrophages attached to titanium implant on osteogenic differentiation of PDLSCs and angiogenesis of HUVECs in vitro.

Xiao L, Wu D, Zhang T, He C, Guo X, Yang H BMC Oral Health. 2024; 24(1):1371.

PMID: 39538267 PMC: 11562097. DOI: 10.1186/s12903-024-05088-7.

Writers, readers, and erasers RNA modifications and drug resistance in cancer.

Chen D, Gu X, Nurzat Y, Xu L, Li X, Wu L Mol Cancer. 2024; 23(1):178.

PMID: 39215288 PMC: 11363509. DOI: 10.1186/s12943-024-02089-6.

References

Coles L, Bartley M, Bert A, Hunter J, Polyak S, Diamond P . A multi-protein complex containing cold shock domain (Y-box) and polypyrimidine tract binding proteins forms on the vascular endothelial growth factor mRNA. Potential role in mRNA stabilization. Eur J Biochem. 2004; 271(3):648-60. DOI: 10.1111/j.1432-1033.2003.03968.x. View

Wang L, Zhou F, Zhang P, Wang H, Qu Z, Jia P . Human type H vessels are a sensitive biomarker of bone mass. Cell Death Dis. 2017; 8(5):e2760. PMC: 5520742. DOI: 10.1038/cddis.2017.36. View

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

Wu R, Feng S, Li F, Shu G, Wang L, Gao P . Transcriptional and post-transcriptional control of autophagy and adipogenesis by YBX1. Cell Death Dis. 2023; 14(1):29. PMC: 9841012. DOI: 10.1038/s41419-023-05564-y. View

Biswas L, Chen J, De Angelis J, Singh A, Owen-Woods C, Ding Z . Lymphatic vessels in bone support regeneration after injury. Cell. 2023; 186(2):382-397.e24. DOI: 10.1016/j.cell.2022.12.031. View

Xue X, Huang J, Yu K, Chen X, He Y, Qi D . YB-1 transferred by gastric cancer exosomes promotes angiogenesis via enhancing the expression of angiogenic factors in vascular endothelial cells. BMC Cancer. 2020; 20(1):996. PMC: 7557103. DOI: 10.1186/s12885-020-07509-6. View

Gu Q, Li Y, Chen Y, Yao P, Ou T . Sciadopitysin: active component from Taxus chinensis for anti-Alzheimer's disease. Nat Prod Res. 2013; 27(22):2157-60. DOI: 10.1080/14786419.2013.790031. View

Xu R, Yallowitz A, Qin A, Wu Z, Shin D, Kim J . Targeting skeletal endothelium to ameliorate bone loss. Nat Med. 2018; 24(6):823-833. PMC: 5992080. DOI: 10.1038/s41591-018-0020-z. View

Chen X, Li A, Sun B, Yang Y, Han Y, Yuan X . 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat Cell Biol. 2019; 21(8):978-990. DOI: 10.1038/s41556-019-0361-y. View

10.

Georgilis A, Klotz S, Hanley C, Herranz N, Weirich B, Morancho B . PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells. Cancer Cell. 2018; 34(1):85-102.e9. PMC: 6048363. DOI: 10.1016/j.ccell.2018.06.007. View

11.

Xiao Y, Cai G, Feng X, Li Y, Guo W, Guo Q . Splicing factor YBX1 regulates bone marrow stromal cell fate during aging. EMBO J. 2023; 42(9):e111762. PMC: 10152142. DOI: 10.15252/embj.2022111762. View

12.

Takahashi M, Shimajiri S, Izumi H, Hirano G, Kashiwagi E, Yasuniwa Y . Y-box binding protein-1 is a novel molecular target for tumor vessels. Cancer Sci. 2010; 101(6):1367-73. PMC: 11159253. DOI: 10.1111/j.1349-7006.2010.01534.x. View

13.

Yang Y, Wang L, Han X, Yang W, Zhang M, Ma H . RNA 5-Methylcytosine Facilitates the Maternal-to-Zygotic Transition by Preventing Maternal mRNA Decay. Mol Cell. 2019; 75(6):1188-1202.e11. DOI: 10.1016/j.molcel.2019.06.033. View

14.

Tuckermann J, Adams R . The endothelium-bone axis in development, homeostasis and bone and joint disease. Nat Rev Rheumatol. 2021; 17(10):608-620. PMC: 7612477. DOI: 10.1038/s41584-021-00682-3. View

15.

Suh K, Lee Y, Kim Y, Choi E . Sciadopitysin protects osteoblast function via its antioxidant activity in MC3T3-E1 cells. Food Chem Toxicol. 2013; 58:220-7. DOI: 10.1016/j.fct.2013.04.028. View

16.

Xu D, Xu S, Kyaw A, Lim Y, Chia S, Siang D . RNA Binding Protein Ybx2 Regulates RNA Stability During Cold-Induced Brown Fat Activation. Diabetes. 2017; 66(12):2987-3000. DOI: 10.2337/db17-0655. View

17.

Fu R, Lv W, Xu Y, Gong M, Chen X, Jiang N . Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis. Nat Commun. 2020; 11(1):460. PMC: 6978338. DOI: 10.1038/s41467-019-14076-3. View

18.

Tikhonova A, Dolgalev I, Hu H, Sivaraj K, Hoxha E, Cuesta-Dominguez A . The bone marrow microenvironment at single-cell resolution. Nature. 2019; 569(7755):222-228. PMC: 6607432. DOI: 10.1038/s41586-019-1104-8. View

19.

Lyabin D, Eliseeva I, Ovchinnikov L . YB-1 protein: functions and regulation. Wiley Interdiscip Rev RNA. 2013; 5(1):95-110. DOI: 10.1002/wrna.1200. View

20.

Cao J, Lu Q, Liu N, Zhang Y, Wang J, Zhang M . Sciadopitysin suppresses RANKL-mediated osteoclastogenesis and prevents bone loss in LPS-treated mice. Int Immunopharmacol. 2017; 49:109-117. DOI: 10.1016/j.intimp.2017.05.029. View