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Theranostics 2021; 11(11):5491-5510. doi:10.7150/thno.55041 This issue Cite

Research Paper

Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss

Rongyao Xu1,2, Xin Shen1,2, Hanyu Xie1,2, Hengguo Zhang1,2, Dingshan Liu1,2, Xin Chen1,2, Yu Fu1,2, Ping Zhang1,2, Yi Yang1,3, Jie Cheng1,2, Hongbing Jiang1,2✉

1. Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
2. Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
3. Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.

✉ Corresponding author: Hongbing Jiang, D.D.S, Ph.D. E-mail: jhbedu.cn; Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu Province 210029, China. Tel: +86-25-85031914; Fax: +86-25-85031910.

Citation:
Xu R, Shen X, Xie H, Zhang H, Liu D, Chen X, Fu Y, Zhang P, Yang Y, Cheng J, Jiang H. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics 2021; 11(11):5491-5510. doi:10.7150/thno.55041. https://www.thno.org/v11p5491.htm
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Abstract

Graphic abstract

Rationale: Postmenopausal-induced bone loss is mainly caused by declining core transcription factors (TFs) of bone mesenchymal stem cells (BMSCs), but little is known about how miRNAs regulate chromatin structure remodeling of TFs gene to maintain BMSCs function in bone homeostasis.

Methods: We examined the serum, salivary and bone samples from Pre- and Post-menopause women by paired analysis and confirmed canonical ceRNA role of MIR143HG and miR-143/145 complexes in cytoplasm and noncanonical role for SOX2 transcription in nucleus (FISH, qRT-PCR, immunostaining, Luciferase assays and ChIP). Moreover, we took advantage of transgenic mice under OVX-induced osteoporosis, studying the in vitro and in vivo effect of miR-143/145 deletion on BMSCs function and bone homeostasis. Last, using miRNA antagonism, antagomiR-143/145 were delivered into bone marrow to treat estrogen-deficient bone loss.

Results: Here, we identified miR-143/145 as potential diagnostic candidates for postmenopausal osteoporosis, and miR-143/145 overexpression impaired BMSCs self-renewing and differentiation function. Mechanistically, we confirmed that cytoplasmic miR-143/145 and LncRNA MIR143HG, that controlled by ERβ, cooperatively regulated pluripotency genes translation via canonical ceRNA pathway, and MIR143HG cooperates with miR‑143 to nuclear translocation for co-activation of SOX2 transcription via opening promoter chromatin. Meanwhile, miR‑143/145 were shuttled into osteoclasts in extracellular vesicles and triggered osteoclastic activity by targeting Cd226 and Srgap2. Furthermore, miR-143/145-/- mice or using chemically‑modified antagomiR-143/145 significantly alleviated estrogen-deficient osteoporosis.

Conclusions: Our findings reveal a canonical and noncanonical role of miR-143/145 in controlling BMSCs pluripotency and unfold their dual effect on bone formation and bone resorption, suggesting miR-143/145 as promising therapeutic targets for treating estrogen-deficient bone loss.

Keywords: Estrogen, Bone Mesenchymal Stem Cells (BMSCs), core transcription factors (TFs), miR-143/145, Extracellular Vesicles (EVs).

Citation styles

APA
Xu, R., Shen, X., Xie, H., Zhang, H., Liu, D., Chen, X., Fu, Y., Zhang, P., Yang, Y., Cheng, J., Jiang, H. (2021). Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics, 11(11), 5491-5510. https://doi.org/10.7150/thno.55041.

ACS
Xu, R.; Shen, X.; Xie, H.; Zhang, H.; Liu, D.; Chen, X.; Fu, Y.; Zhang, P.; Yang, Y.; Cheng, J.; Jiang, H. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics 2021, 11 (11), 5491-5510. DOI: 10.7150/thno.55041.

NLM
Xu R, Shen X, Xie H, Zhang H, Liu D, Chen X, Fu Y, Zhang P, Yang Y, Cheng J, Jiang H. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics 2021; 11(11):5491-5510. doi:10.7150/thno.55041. https://www.thno.org/v11p5491.htm

CSE
Xu R, Shen X, Xie H, Zhang H, Liu D, Chen X, Fu Y, Zhang P, Yang Y, Cheng J, Jiang H. 2021. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics. 11(11):5491-5510.

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