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Endocrine, Metabolic & Immune Disorders - Drug Targets


ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Letter Article

MiR-12200-5p Targets Multiple Members of Wnt Signaling Pathway to Inhibit Osteoblast Differentiation and Bone Formation

Author(s): Hui Li, Chong Yin, Jingjia Li, Qian Huang, Ying Huai, Xiaohua Chu, Mili Ji, Ye Tian*, Airong Qian* and Danming Li*

Volume 23, Issue 10, 2023

Published on: 18 May, 2023

Page: [1254 - 1264] Pages: 11

DOI: 10.2174/1871530323666230301150350

Price: $65


Background: Osteoporosis is widespread and has become an emerging problem in the elderly. MicroRNAs could affect osteoblast differentiation and further regulate the occurrence of osteoporosis by targeting osteogenic differentiation signaling pathways. Our screening study found that miR-12200-5p simultaneously targeted six important factors within the Wnt signaling pathway (Apc, Tcf4, Tcf7, Wnt3a, Wnt5a, and Lrp6), indicating that miR-12200-5p might function as a strong regulator of this pathway. Since the Wnt pathway exists as one of the most essential pathways for osteogenic differentiation, miR-12200-5p may have an important role in the development of osteoporosis.

Objective: This study intended to explore the regulatory role and corresponding mechanism of miR-12200-5p in osteoblast differentiation.

Methods: We investigated the differentiation of osteoblast after the treatments of miR-12200-5p mimic and inhibitor. The interactions between miR-12200-5p and its target genes were also detected. Furthermore, the rescue effect of miR-12200-5p inhibitor on osteoporosis was evaluated using an ovariectomized osteoporosis mouse model.

Results: MiR-12200-5p significantly inhibited osteoblast differentiation, and bound with the 3’-UTR sequences of its target genes (Apc, Tcf4, Tcf7, Wnt3a, Wnt5a, and Lrp6) to reduce the expressions of these genes. The inhibition of miR-12200-5p would almost fully alleviate postmenopausal osteoporosis.

Conclusion: MiR-12200-5p could strongly repress osteoblast differentiation and bone formation by targeting multiple members of the Wnt signaling pathway simultaneously. The study supplemented the theoretical and experimental basis for researching the mechanism of osteogenic differentiation and inspired the development of novel therapeutic strategies for osteoporosis.

Keywords: miR-12200-5p, Wnt signaling pathway, simultaneous targeting, osteoblast differentiation, bone formation, osteoporosis.

Graphical Abstract
Cheng, C.; Wentworth, K.; Shoback, D.M. New frontiers in osteoporosis therapy. Annu. Rev. Med., 2020, 71(1), 277-288.
[] [PMID: 31509477]
Yang, T.L.; Shen, H.; Liu, A.; Dong, S.S.; Zhang, L.; Deng, F.Y.; Zhao, Q.; Deng, H.W. A road map for understanding molecular and genetic determinants of osteoporosis. Nat. Rev. Endocrinol., 2020, 16(2), 91-103.
[] [PMID: 31792439]
Iolascon, G.; Moretti, A.; Toro, G.; Gimigliano, F.; Liguori, S.; Paoletta, M. Pharmacological therapy of osteoporosis: What’s new? Clin. Interv. Aging, 2020, 15, 485-491.
[] [PMID: 32273690]
Chotiyarnwong, P.; McCloskey, E.V. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat. Rev. Endocrinol., 2020, 16(8), 437-447.
[] [PMID: 32286516]
Al Saedi, A.; Stupka, N.; Duque, G. Pathogenesis of osteoporosis. Handb. Exp. Pharmacol., 2020, 262, 353-367.
[] [PMID: 32297003]
Li, X.; Xu, J.; Dai, B.; Wang, X.; Guo, Q.; Qin, L. Targeting autophagy in osteoporosis: From pathophysiology to potential therapy. Ageing Res. Rev., 2020, 62, 101098.
[] [PMID: 32535273]
Reid, I.R. A broader strategy for osteoporosis interventions. Nat. Rev. Endocrinol., 2020, 16(6), 333-339.
[] [PMID: 32203407]
Amjadi-Moheb, F.; Akhavan-Niaki, H. Wnt signaling pathway in osteoporosis: Epigenetic regulation, interaction with other signaling pathways, and therapeutic promises. J. Cell. Physiol., 2019, 234(9), 14641-14650.
[] [PMID: 30693508]
Karner, C.M.; Long, F. Wnt signaling and cellular metabolism in osteoblasts. Cell. Mol. Life Sci., 2017, 74(9), 1649-1657.
[] [PMID: 27888287]
Mäkitie, R.E.; Hackl, M.; Niinimäki, R.; Kakko, S.; Grillari, J.; Mäkitie, O. Altered microRNA profile in osteoporosis caused by impaired WNT signaling. J. Clin. Endocrinol. Metab., 2018, 103(5), 1985-1996.
[] [PMID: 29506076]
Han, J.; Wang, Y.; Zhou, H.; Zhang, Y.; Wan, D. CD137 regulates bone loss via the p53 Wnt/β-catenin signaling pathways in aged mice. Front. Endocrinol., 2022, 13, 922501.
[] [PMID: 35846320]
Jilek, J.L.; Tian, Y.; Yu, A.M. Effects of MicroRNA-34a on the pharmacokinetics of cytochrome P450 probe drugs in mice. Drug Metab. Dispos., 2017, 45(5), 512-522.
[] [PMID: 28254952]
Li, X.; Tian, Y.; Tu, M.J.; Ho, P.Y.; Batra, N.; Yu, A.M. Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression. Acta Pharm. Sin. B, 2019, 9(3), 639-647.
[] [PMID: 31193825]
Yu, A.M.; Tian, Y.; Tu, M.J.; Ho, P.Y.; Jilek, J.L. MicroRNA pharmacoepigenetics: Posttranscriptional regulation mechanisms behind variable drug disposition and strategy to develop more effective therapy. Drug Metab. Dispos., 2016, 44(3), 308-319.
[] [PMID: 26566807]
Xu, Y.; Zhang, S.; Guo, J.; Chen, L.; Liou, Y.; Rao, T.; Peng, J.; Guo, Y.; Huang, W.; Tan, Z.; Ou-yang, D.; Zhou, H.; Zhang, W.; Chen, Y. A joint technology combining the advantages of capillary microsampling with mass spectrometry applied to the trans-resveratrol pharmacokinetic study in mice. J. Anal. Methods Chem., 2022, 2022, 1-11.
[] [PMID: 35083093]
Li, D.; Liu, J.; Guo, B.; Liang, C.; Dang, L.; Lu, C.; He, X.; Cheung, H.Y.S.; Xu, L.; Lu, C.; He, B.; Liu, B.; Shaikh, A.B.; Li, F.; Wang, L.; Yang, Z.; Au, D.W.T.; Peng, S.; Zhang, Z.; Zhang, B.T.; Pan, X.; Qian, A.; Shang, P.; Xiao, L.; Jiang, B.; Wong, C.K.C.; Xu, J.; Bian, Z.; Liang, Z.; Guo, D.; Zhu, H.; Tan, W.; Lu, A.; Zhang, G. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat. Commun., 2016, 7(1), 10872.
[] [PMID: 26947250]
Wang, X.; Guo, B.; Li, Q.; Peng, J.; Yang, Z.; Wang, A.; Li, D.; Hou, Z.; Lv, K.; Kan, G.; Cao, H.; Wu, H.; Song, J.; Pan, X.; Sun, Q.; Ling, S.; Li, Y.; Zhu, M.; Zhang, P.; Peng, S.; Xie, X.; Tang, T.; Hong, A.; Bian, Z.; Bai, Y.; Lu, A.; Li, Y.; He, F.; Zhang, G.; Li, Y. miR-214 targets ATF4 to inhibit bone formation. Nat. Med., 2013, 19(1), 93-100.
[] [PMID: 23223004]
Zhuo, Z.; Wan, Y.; Guan, D.; Ni, S.; Wang, L.; Zhang, Z.; Liu, J.; Liang, C.; Yu, Y.; Lu, A.; Zhang, G.; Zhang, B.T. A loop-based and AGO-incorporated virtual screening model targeting AGO-mediated miRNA-mRNA interactions for drug discovery to rescue bone phenotype in genetically modified mice. Adv. Sci., 2020, 7(13), 1903451.
[] [PMID: 32670749]
John, A.A.; Xie, J.; Yang, Y.S.; Kim, J.M.; Lin, C.; Ma, H.; Gao, G.; Shim, J.H. AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy. Mol. Ther. Nucleic Acids, 2022, 29, 296-311.
[] [PMID: 35950212]
Basak, I.; Bhatlekar, S.; Manne, B.K.; Stoller, M.; Hugo, S.; Kong, X.; Ma, L.; Rondina, M.T.; Weyrich, A.S.; Edelstein, L.C.; Bray, P.F. miR-15a-5p regulates expression of multiple proteins in the megakaryocyte GPVI signaling pathway. J. Thromb. Haemost., 2019, 17(3), 511-524.
[] [PMID: 30632265]
Tiwari, A.; Mukherjee, B.; Dixit, M. MicroRNA key to angiogenesis regulation: MiRNA biology and therapy. Curr. Cancer Drug Targets, 2018, 18(3), 266-277.
[] [PMID: 28669338]
Lamin, V.; Verry, J.; Dokun, O.S.; Kronemberger, A.; Wong, T.; Lira, V.A.; Dokun, A.O. microRNA‐29a regulates ADAM12 through direct interaction with ADAM12 mRNA and modulates postischemic perfusion recovery. J. Am. Heart Assoc., 2022, 11(16), e025727.
[] [PMID: 35946473]
Yin, C.; Tian, Y.; Yu, Y.; Wang, H.; Wu, Z.; Huang, Z.; Zhang, Y.; Li, D.; Yang, C.; Wang, X.; Li, Y.; Qian, A. A novel long noncoding RNA AK016739 inhibits osteoblast differentiation and bone formation. J. Cell. Physiol., 2019, 234(7), 11524-11536.
[] [PMID: 30656695]
Yu, S.; Geng, Q.; Ma, J.; Sun, F.; Yu, Y.; Pan, Q.; Hong, A. Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation. Cell Death Dis., 2013, 4(10), e868.
[] [PMID: 24136232]
Bellavia, D.; Salamanna, F.; Raimondi, L.; De Luca, A.; Carina, V.; Costa, V.; Alessandro, R.; Fini, M.; Giavaresi, G. Deregulated miRNAs in osteoporosis: Effects in bone metastasis. Cell. Mol. Life Sci., 2019, 76(19), 3723-3744.
[] [PMID: 31147752]
Ensrud, K.E.; Crandall, C. J. Osteoporosis. Ann. Intern. Med., 2017, 167(3), ITC17-ITC32.
[] [PMID: 28761958]
Wang, J.; Xiao, L.; Wang, W.; Zhang, D.; Ma, Y.; Zhang, Y.; Wang, X. The auxiliary role of heparin in bone regeneration and its application in bone substitute materials. Front. Bioeng. Biotechnol., 2022, 10, 837172.
[] [PMID: 35646879]
Black, D.M.; Rosen, C.J. Clinical practice. Postmenopausal osteoporosis. N. Engl. J. Med., 2016, 374(3), 254-262.
[] [PMID: 26789873]
van Wijnen, A.J.; van de Peppel, J.; van Leeuwen, J.P.; Lian, J.B.; Stein, G.S.; Westendorf, J.J.; Oursler, M.J.; Im, H.J.; Taipaleenmaki, H.; Hesse, E. MicroRNA functions in osteogenesis and dysfunctions in osteoporosis. Curr Osteoporos Rep, 2013, 11(2), 72-82.
[] [PMID: 23605904]
Chen, Z.; Zhao, F.; Liang, C.; Hu, L.; Li, D.; Zhang, Y.; Yin, C.; Chen, L.; Wang, L.; Lin, X.; Su, P.; Ma, J.; Yang, C.; Tian, Y.; Zhang, W.; Li, Y.; Peng, S.; Chen, W.; Zhang, G.; Qian, A. Silencing of miR-138-5p sensitizes bone anabolic action to mechanical stimuli. Theranostics, 2020, 10(26), 12263-12278.
[] [PMID: 33204341]
Ma, J.; Lin, X.; Chen, C.; Li, S.; Zhang, S.; Chen, Z.; Li, D.; Zhao, F.; Yang, C.; Yin, C.; Qiu, W.; Xiao, Y.; Zhang, K.; Miao, Z.; Yang, T.; Qian, A. Circulating miR-181c-5p and miR-497-5p are potential biomarkers for prognosis and diagnosis of osteoporosis. J. Clin. Endocrinol. Metab., 2020, 105(5), 1445-1460.
[] [PMID: 31872255]
Kim, H-Y.; Yoon, J-Y.; Yun, J-H.; Cho, K-W.; Lee, S-H.; Rhee, Y-M.; Jung, H-S.; Lim, H.J.; Lee, H.; Choi, J.; Heo, J-N.; Lee, W.; No, K.T.; Min, D.; Choi, K-Y. CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation. Cell Death Differ., 2015, 22(6), 912-920.
[] [PMID: 25633194]
Long, F. Building strong bones: Molecular regulation of the osteoblast lineage. Nat. Rev. Mol. Cell Biol., 2012, 13(1), 27-38.
[] [PMID: 22189423]
Rachner, T.D.; Khosla, S.; Hofbauer, L.C. Osteoporosis: Now and the future. Lancet, 2011, 377(9773), 1276-1287.
[] [PMID: 21450337]
Regard, J.B.; Zhong, Z.; Williams, B.O.; Yang, Y. Wnt signaling in bone development and disease: Making stronger bone with Wnts. Cold Spring Harb. Perspect. Biol., 2012, 4(12), a007997.
[] [PMID: 23209148]
Liang, D.; Song, G.; Zhang, Z. miR 216a 3p inhibits osteogenic differentiation of human adipose derived stem cells via Wnt3a in the Wnt/β-catenin signaling pathway. Exp. Ther. Med., 2022, 23(4), 309.
[] [PMID: 35340869]
Yin, C.; Tian, Y.; Yu, Y.; Li, D.; Miao, Z.; Su, P.; Zhao, Y.; Wang, X.; Pei, J.; Zhang, K.; Qian, A. Long noncoding RNA AK039312 and AK079370 inhibits bone formation via miR-199b-5p. Pharmacol. Res., 2020, 163, 105230.
[] [PMID: 33031910]
Yin, C.; Tian, Y.; Yu, Y.; Yang, C.; Su, P.; Zhao, Y.; Wang, X.; Zhang, K.; Pei, J.; Li, D.; Chen, Z.; Zhang, Y.; Miao, Z.; Qian, A. miR-129-5p inhibits bone formation through TCF4. Front. Cell Dev. Biol., 2020, 8, 600641.
[] [PMID: 33240893]
Mahmood, S.; Bhatti, A.; Syed, N.A.; John, P. The microRNA regulatory network: A far-reaching approach to the regulate the Wnt signaling pathway in number of diseases. J. Recept. Signal Transduct. Res., 2016, 36(3), 310-318.
[] [PMID: 26523375]
Sun, Q.; Liu, S.; Feng, J.; Kang, Y.; Zhou, Y.; Guo, S. Current status of MicroRNAs that target the wnt signaling pathway in regulation of osteogenesis and bone metabolism: A review. Med. Sci. Monit., 2021, 27, e929510.
[] [PMID: 33828067]

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