AI Chat Paper
Discover the SciOpen Platform and Achieve Your Research Goals with Ease.
Search articles, authors, keywords, DOl and etc.
{{expandStatus?'Exit ':''}}Advanced Search
Postmenopausal osteoporosis is a common bone metabolic disorder characterized by deterioration of the bone microarchitecture, leading to an increased risk of fractures. Recently, circular RNAs (circRNAs) have been demonstrated to play pivotal roles in regulating bone metabolism. However, the underlying functions of circRNAs in bone metabolism in postmenopausal osteoporosis remain obscure. Here, we report that circStag1 is a critical osteoporosis-related circRNA that shows significantly downregulated expression in osteoporotic bone marrow mesenchymal stem cells (BMSCs) and clinical bone tissue samples from patients with osteoporosis. Overexpression of circStag1 significantly promoted the osteogenic capability of BMSCs. Mechanistically, we found that circStag1 interacts with human antigen R (HuR), an RNA-binding protein, and promotes the translocation of HuR into the cytoplasm. A high cytoplasmic level of HuR led to the activation of the Wnt signaling pathway by stabilizing and enhancing low-density lipoprotein receptor-related protein 5/6 (Lrp5/6) and β-catenin expression, thereby stimulating the osteogenic differentiation of BMSCs. Furthermore, overexpression of circStag1 in vivo by circStag1-loaded adeno-associated virus (circStag1-AAV) promoted new bone formation, thereby preventing bone loss in ovariectomized rats. Collectively, we show that circStag1 plays a pivotal role in promoting the regeneration of bone tissue via HuR/Wnt signaling, which may provide new strategies to prevent bone metabolic disorders such as postmenopausal osteoporosis.
Black, D. M. & Rosen, C. J. Clinical practice. postmenopausal osteoporosis. N. Engl. J. Med. 374, 254–262 (2016).
Yardimci, A., Ozdede, M. R. & Kelestimur, H. Agomelatine, A potential multi-target treatment alternative for insomnia, depression, and osteoporosis in postmenopausal women: a hypothetical model. Front. Psychiatry 12, 654616 (2021).
Armas, L. A. & Recker, R. R. Pathophysiology of osteoporosis: new mechanistic insights. Endocrinol. Metab. Clin. North Am. 41, 475–486 (2012).
Crandall, C. J. et al. Serial bone density measurement and incident fracture risk discrimination in postmenopausal women. JAMA Intern. Med. 180, 1232–1240 (2020).
Barron, R. L., Oster, G., Grauer, A., Crittenden, D. B. & Weycker, D. Determinants of imminent fracture risk in postmenopausal women with osteoporosis. Osteoporos. Int. 31, 2103–2111 (2020).
Black, D. M. & Rosen, C. J. Clinical practice. Postmenopausal osteoporosis. N. Engl. J. Med. 374, 254–362 (2016).
Snyder, S. Bisphosphonates for osteopenia in postmenopausal women. JAMA 323, 1096 (2020).
Ensrud, K. E. Bisphosphonates for postmenopausal osteoporosis. JAMA 325, 96 (2021).
Otto, S. et al. A drug holiday reduces the frequency and severity of medication-related osteonecrosis of the jaw in a minipig model. J. Bone Min. Res. 35, 2179–2192 (2020).
Wan, J. T., Sheeley, D. M., Somerman, M. J. & Lee, J. S. Mitigating osteonecrosis of the jaw (ONJ) through preventive dental care and understanding of risk factors. Bone Res. 8, 14 (2020).
Krzeszinski, J. Y. et al. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature 512, 431–435 (2014).
Li, M. et al. A novel lncRNA LNC_000052 leads to the dysfunction of osteoporotic BMSCs via the miR-96-5p-PIK3R1 axis. Cell Death Dis. 11, 795 (2020).
Sun, M. et al. Circulating microRNA-19b identified from osteoporotic vertebral compression fracture patients increases bone formation. J. Bone Min. Res. 35, 306–316 (2020).
Xu, R. et al. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics 11, 5491–5510 (2021).
Baumann, K. CircRNAs in lifespan. Nat. Rev. Mol. Cell Biol. 21, 420 (2020).
Zhao, Q. et al. Targeting mitochondria-located circRNA SCAR alleviates NASH via reducing mROS output. Cell 183, 76–93.e22 (2020).
Kristensen, L. S. et al. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 20, 675–691 (2019).
Gu, Y. et al. Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling. Mol. Cancer 20, 132 (2021).
Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).
Chen, G. et al. Circular RNA CDR1as promotes adipogenic and suppresses osteogenic differentiation of BMSCs in steroid-induced osteonecrosis of the femoral head. Bone 133, 115258 (2020).
Zeng, Z. et al. Circular RNA CircMAP3K5 acts as a MicroRNA-22-3p sponge to promote resolution of intimal hyperplasia via TET2-mediated smooth muscle cell differentiation. Circulation 143, 354–371 (2021).
Guarnerio, J. et al. Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res. 29, 628–640 (2019).
Huang, A., Zheng, H., Wu, Z., Chen, M. & Huang, Y. Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics 10, 3503–3517 (2020).
Shen, S. et al. circPDE4B prevents articular cartilage degeneration and promotes repair by acting as a scaffold for RIC8A and MID1. Ann. Rheum. Dis. 80, 1209–1219 (2021).
Chen, G. et al. Promising diagnostic and therapeutic circRNAs for skeletal and chondral disorders. Int J. Biol. Sci. 17, 1428–1439 (2021).
Shao, T., Pan, Y. H. & Xiong, X. D. Circular RNA: an important player with multiple facets to regulate its parental gene expression. Mol. Ther. Nucleic Acids 23, 369–376 (2021).
Huang, R. et al. N6-methyladenosine modification of fatty acid amide hydrolase messenger RNA in circular RNA STAG1-regulated astrocyte dysfunction and depressive-like behaviors. Biol. Psychiatry 88, 392–404 (2020).
Wu, M., Tong, C., Yan, W., To, K. & Cho, W. The RNA binding protein HuR: a promising drug target for anticancer therapy. Curr. Cancer Drug Targets 19, 382–399 (2019).
Liu, L. et al. RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway. Mol. Biol. Cell 25, 3308–3318 (2014).
Lai, K. et al. Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6. Gastroenterology 152, 1477–1491 (2017).
Shu, C. et al. Long noncoding RNA lncARSR promotes epithelial ovarian cancer cell proliferation and invasion by association with HuR and miR-200 family. Am. J. Cancer Res. 8, 981–992 (2018).
Palomo-Irigoyen, M. et al. HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis. J. Clin. Invest. 130, 3848–3864 (2020).
Yang, Q., Li, F., He, A. T. & Yang, B. B. Circular RNAs: expression, localization, and therapeutic potentials. Mol. Ther. 29, 1683–1702 (2021).
Yu, L. & Liu, Y. circRNA_0016624 could sponge miR-98 to regulate BMP2 expression in postmenopausal osteoporosis. Biochem. Biophys. Res. Commun. 516, 546–550 (2019).
Wen, J. et al. Circular RNA hsa_circ_0076906 competes with OGN for miR-1305 biding site to alleviate the progression of osteoporosis. Int J. Biochem. Cell Biol. 122, 105719 (2020).
Tang, X. et al. Review on circular RNAs and new insights into their roles in cancer. Comput Struct. Biotechnol. J. 19, 910–928 (2021).
Liu, B. et al. CircBACH1 (hsa_circ_0061395) promotes hepatocellular carcinoma growth by regulating p27 repression via HuR. J. Cell Physiol. 235, 6929–6941 (2020).
Grammatikakis, I., Abdelmohsen, K. & Gorospe, M. Posttranslational control of HuR function. Wiley Interdiscip. Rev. RNA. 8, e1372 (2017).
Schultz, C. W., Preet, R., Dhir, T., Dixon, D. A. & Brody, J. R. Understanding and targeting the disease-related RNA binding protein human antigen R (HuR). Wiley Interdiscip. Rev. RNA 11, e1581 (2020).
Abdelmohsen, K. et al. Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biol. 14, 361–369 (2017).
Chen, Y. et al. Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes. Cell Death Differ. 26, 1346–1364 (2019).
Yang, F. et al. Circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation. Mol. Cancer 18, 158 (2019).
Li, X. X. et al. Interaction between HuR and circPABPN1 modulates autophagy in the intestinal epithelium by altering ATG16L1 translation. Mol. Cell Biol. 40, e00492–19 (2020).
Liang, Y. et al. circDCUN1D4 suppresses tumor metastasis and glycolysis in lung adenocarcinoma by stabilizing TXNIP expression. Mol. Ther. Nucleic Acids 23, 355–368 (2021).
Li, Y. et al. Post-transcriptional regulation of Wnt co-receptor LRP6 and RNA-binding protein HuR by miR-29b in intestinal epithelial cells. Biochem. J. 473, 1641–1649 (2016).
Chai, W., Liu, R., Li, F., Zhang, Z. & Lei, B. Long noncoding RNA TSLNC8 enhances pancreatic cancer aggressiveness by regulating CTNNB1 expression via association with HuR. Hum. Cell 34, 165–176 (2021).
Garikipati, V. et al. Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis. Nat. Commun. 10, 4317 (2019).
Diling, C. et al. CircNF1-419 improves the gut microbiome structure and function in AD-like mice. Aging 12, 260–287 (2020).
Dai, J. & Rabie, A. B. Recombinant adeno-associated virus vector hybrids efficiently target different skeletal cells. Front. Biosci. 12, 4280–4287 (2007).
Li, W. Y. et al. KLF7 overexpression in bone marrow stromal stem cells graft transplantation promotes sciatic nerve regeneration. J. Neural. Eng. 16, 056011 (2019).
Xia, P. et al. TGF-β1-induced chondrogenesis of bone marrow mesenchymal stem cells is promoted by low-intensity pulsed ultrasound through the integrin-mTOR signaling pathway. Stem Cell Res. Ther. 8, 281 (2017).
Zhu, P. et al. IL-13 secreted by ILC2s promotes the self-renewal of intestinal stem cells through circular RNA circPan3. Nat. Immunol. 20, 183–194 (2019).
Popenda, M. et al. Automated 3D structure composition for large RNAs. Nucleic Acids Res. 40, e112 (2012).
Antczak, M. et al. New functionality of RNAComposer: an application to shape the axis of miR160 precursor structure. Acta Biochim. Pol. 63, 737–744 (2016).
Zakov, S., Goldberg, Y., Elhadad, M. & Ziv-Ukelson, M. Rich parameterization improves RNA structure prediction. J. Comput. Biol. 18, 1525–1542 (2011).
Ripin, N. et al. Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM. Proc. Natl Acad. Sci. USA 116, 2935–2944 (2019).
van Zundert, G. et al. The HADDOCK2.2 web server: user-friendly integrative modeling of biomolecular complexes. J. Mol. Biol. 428, 720–725 (2016).
Meganck, R. M. et al. Tissue-dependent expression and translation of circular RNAs with recombinant AAV vectors in vivo. Mol. Ther. Nucleic Acids 13, 89–98 (2018).
Challis, R. C. et al. Systemic AAV vectors for widespread and targeted gene delivery in rodents. Nat. Protoc. 14, 379–414 (2019).
Schamel, M., Barralet, J. E., Gelinsky, M., Groll, J. & Gbureck, U. Intrinsic 3D prestressing: a new route for increasing strength and improving toughness of hybrid inorganic biocements. Adv. Mater. 29, 1701035 (2017).
139
Views
1
Downloads
36
Crossref
39
Web of Science
39
Scopus
0
CSCD
Altmetrics
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
京公网安备11010802044758号