LncRNA Nron regulates osteoclastogenesis during orthodontic bone resorption

Abstract

Activation of osteoclasts during orthodontic tooth treatment is a prerequisite for alveolar bone resorption and tooth movement. However, the key regulatory molecules involved in osteoclastogenesis during this process remain unclear. Long noncoding RNAs (lncRNAs) are a newly identified class of functional RNAs that regulate cellular processes, such as gene expression and translation regulation. Recently, lncRNAs have been reported to be involved in osteogenesis and bone formation. However, as the most abundant noncoding RNAs in vivo, the potential regulatory role of lncRNAs in osteoclast formation and bone resorption urgently needs to be clarified. We recently found that the lncRNA Nron (long noncoding RNA repressor of the nuclear factor of activated T cells) is highly expressed in osteoclast precursors. Nron is downregulated during osteoclastogenesis and bone ageing. To further determine whether Nron regulates osteoclast activity during orthodontic treatment, osteoclastic Nron transgenic (Nron cTG) and osteoclastic knockout (Nron CKO) mouse models were generated. When Nron was overexpressed, the orthodontic tooth movement rate was reduced. In addition, the number of osteoclasts decreased, and the activity of osteoclasts was inhibited. Mechanistically, Nron controlled the maturation of osteoclasts by regulating NFATc1 nuclear translocation. In contrast, by deleting Nron specifically in osteoclasts, tooth movement speed increased in Nron CKO mice. These results indicate that lncRNAs could be potential targets to regulate osteoclastogenesis and orthodontic tooth movement speed in the clinic in the future.

References

[1] Baloul SS. Osteoclastogenesis and osteogenesis during tooth movement. Front. Oral Biol., 2016, 18: 75-79.

[2] Tompkins KA. The osteoimmunology of alveolar bone loss. Connect. Tissue Res., 2016, 57: 69-90.

[3] Papathanasiou E, Kantarci A, Konstantinidis A, Gao H, Van Dyke TE. SOCS-3 regulates alveolar bone loss in experimental periodontitis. J. Dent. Res., 2016, 95: 1018-1025.

[4] Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol. Med., 2006, 12: 17-25.

[5] Erkhembaatar M, . Lysosomal Ca(2+) signaling is essential for osteoclastogenesis and bone remodeling. J. Bone Miner. Res., 2017, 32: 385-396.

[6] Quach JM, . Myelosuppressive therapies significantly increase pro-inflammatory cytokines and directly cause bone loss. J. Bone Miner. Res., 2015, 30: 886-897.

[7] Yamaguchi M, Kasai K. Inflammation in periodontal tissues in response to mechanical forces. Arch. Immunol. Ther. Exp. (Warsz.), 2005, 53: 388-398.

[8] Cheng P, . miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B. J. Bone Miner. Res., 2013, 28: 1180-1190.

[9] Lee Y, . MicroRNA-124 regulates osteoclast differentiation. Bone, 2013, 56: 383-389.

[10] Rossi M, . miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease. J. Cell Physiol., 2013, 228: 1506-1515.

[11] Yan B, . Long noncoding RNAs: versatile players in biologcial processes and human disorders. Epigenomics, 2014, 6: 375-379.

[12] Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat. Rev. Genet., 2009, 10: 155-159.

[13] Zhu L, Xu PC. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem. Biophys. Res. Commun., 2013, 432: 612-617.

[14] Zhang J, Tao Z, Wang Y. Long noncoding RNA DANCR regulates the proliferation and osteogenic differentiation of human bone-derived marrow mesenchymal stem cells via the p38 MAPK pathway. Int. J. Mol. Med., 2018, 41: 213-219.

[15] Wu QY, . Long non-coding RNAs: a new regulatory code for osteoporosis. Front. Endocrinol., 2018, 9: 587.

[16] Li J, . Long noncoding RNA NRON contributes to HIV-1 latency by specifically inducing tat protein degradation. Nat. Commun., 2016, 7

[17] Willingham AT, . A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science, 2005, 309: 1570-1573.

[18] Takayanagi H, . Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell, 2002, 3: 889-901.

[19] Feng W, Guo J, Li M. RANKL-independent modulation of osteoclastogenesis. J. Oral. Biosci., 2019, 61: 16-21.

[20] Feng Q, Zheng S, Zheng J. The emerging role of microRNAs in bone remodeling and its therapeutic implications for osteoporosis. Biosci. Rep., 2018, 38: BSR20180453.

[21] Clark BS, Blackshaw S. Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease. Front. Genet., 2014, 5: 164.

[22] Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell, 2016, 29: 452-463.

[23] Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol., 2011, 21: 354-361.

[24] Yu C, . LncRNA TUG1 sponges miR-204-5p to promote osteoblast differentiation through upregulating Runx2 in aortic valve calcification. Cardiovasc. Res., 2018, 114: 168-179.

[25] Barter MJ, . The long non-coding RNA ROCR contributes to SOX9 expression and chondrogenic differentiation of human mesenchymal stem cells. Development, 2017, 144: 4510-4521.

[26] Huynh NP, Anderson BA, Guilak F, McAlinden A. Emerging roles for long noncoding RNAs in skeletal biology and disease. Connect. Tissue Res., 2017, 58: 116-141.

[27] Wang Q, . LncRNA MEG3 inhibited osteogenic differentiation of bone marrow mesenchymal stem cells from postmenopausal osteoporosis by targeting miR-133a-3p. Biomed. Pharmacother., 2017, 89: 1178-1186.

[28] Dou C, . Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis. Sci. Rep., 2016, 6

[29] Tong X, Gu PC, Xu SZ, Lin XJ. Long non-coding RNA-DANCR in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis. Biosci. Biotechnol. Biochem., 2015, 79: 732-737.

[30] Xiao X, . LncRNA MALAT1 sponges miR-204 to promote osteoblast differentiation of human aortic valve interstitial cells through up-regulating Smad4. Int. J. Cardiol., 2017, 243: 404-412.

[31] Yao Z, . Long non-coding RNA NRON is downregulated in HCC and suppresses tumour cell proliferation and metastasis. Biomed. Pharmacother., 2018, 104: 102-109.

[32] Xuan L, . Circulating long non-coding RNAs NRON and MHRT as novel predictive biomarkers of heart failure. J. Cell. Mol. Med., 2017, 21: 1803-1814.

[33] Melbourne JK, Chase KA, Feiner B, Rosen C, Sharma RP. Long non-coding and endogenous retroviral RNA levels are associated with proinflammatory cytokine mRNA expression in peripheral blood cells: implications for schizophrenia. Psychiatry Res., 2018, 262: 465-468.

[34] Shou J, . Nuclear factor of activated T cells in cancer development and treatment. Cancer Lett., 2015, 361: 174-184.

[35] Tang YY, Wo LK, Chai H. Effects of noncoding RNA NRON gene regulation on human umbilical vein endothelial cells functions. Zhonghua Xin Xue Guan Bing. Za Zhi, 2013, 41: 245-250.

[36] Sharma S, . Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc. Natl Acad. Sci. USA, 2011, 108: 11381-11386.

[37] Matsumoto M, . Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J. Biol. Chem., 2004, 279: 45969-45979.

[38] Kim K, . Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activation-induced cytokine-mediated osteoclastogenesis. J. Biol. Chem., 2005, 280: 35209-35216.

[39] Kim Y, . Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis. J. Biol. Chem., 2005, 280: 32905-32913.

[40] Cao H, . Force-induced Adrb2 in periodontal ligament cells promotes tooth movement. J. Dent. Res., 2014, 93: 1163-1169.

Funding

National Science and Techonology Major Project of China (2016YFC1102705); Special Fund of Chinese Central University for Basic Scientific Research (20173386); Training program of Shanghai Municipal Health System for Excellent Talents (2017BR009)

National Natural Science Foundation of China (National Science Foundation of China)(81822012, 81771043, 81771043, 81771043, 81771043)

National Science and Techonology Major Project of China (2016YFC1102705); Training program of Shanghai Municipal Health System for Excellent Talents (2017BR009)