• 四川大學(xué)華西醫(yī)院內(nèi)分泌代謝病研究室（成都，610041）;

目的 總結(jié)微小RNA（microRNA，miRNA）在成骨細(xì)胞分化成熟過程中的調(diào)控作用及作用機(jī)制，為相關(guān)的基礎(chǔ)和臨床研究提供參考。 方法 廣泛查閱近年miRNA 對成骨分化調(diào)節(jié)相關(guān)研究文獻(xiàn)，對成骨細(xì)胞分化成熟過程中的功能性miRNA 進(jìn)行分類和總結(jié)。 結(jié)果 miRNA 分子參與了成骨細(xì)胞分化成熟過程中的各個(gè)階段，通過調(diào)節(jié)BMP、TGF-β、Wnt/β-catenin 等一系列信號通路調(diào)控成骨細(xì)胞的分化成熟。在病理狀況下，尤其是一些成骨細(xì)胞分化紊亂引起的疾病中能觀察到相關(guān)miRNA 分子的異常表達(dá)。 結(jié)論 miRNA 在成骨細(xì)胞分化成熟過程中的生理病理作用將為骨代謝相關(guān)疾病的早期診斷和靶向治療提供新的思路和手段。

引用本文： 周名亮,李謐,余希杰. 微小RNA對成骨細(xì)胞分化成熟的調(diào)控及臨床意義. 中國修復(fù)重建外科雜志, 2012, 26(6): 755-759. doi: 復(fù)制

1. Tiscornia G, Izpisúa Belmonte JC. MicroRNAs in embryonic stem cell function and fate. Genes Dev, 2010, 24(24): 2732-2741.
2. Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell, 2008, 133(2): 217-222.
3. Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu Rev Cell Dev Biol, 2009, 25: 629-648.
4. Baek WY, Kim JE. Transcriptional regulation of bone formation. Front Biosci (Schol Ed), 2011, 3: 126-135.
5. Griffiths-Jones S, Saini HK, van Dongen S, et al. miRBase: tools for microRNA genomics. Nucleic Acids Res, 2008, 36(Database issue): D154-158.
6. Komori T. Signaling networks in RUNX2-dependent bone development. J Cell Biochem, 2011, 112(3): 750-755.
7. Chen Y, Alman BA. Wnt pathway, an essential role in bone regeneration. J Cell Biochem, 2009, 106(3): 353-362.
8. Jiménez MJ, Balbín M, López JM, et al. Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Mol Cell Biol, 1999, 19(6): 4431-4442.
9. Thirunavukkarasu K, Halladay DL, Miles RR, et al. The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function. J Biol Chem, 2000, 275(33): 25163-25172.
10. Oskowitz AZ, Lu J, Penfornis P, et al. Human multipotent stromal cells from bone marrow and microRNA: regulation of differentiation and leukemia inhibitory factor expression. Proc Natl Acad Sci U S A, 2008, 105(47): 18372-18377.
11. Gaur T, Hussain S, Mudhasani R, et al. Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse. Dev Biol, 2010, 340(1): 10-21.
12. Mizuno Y, Yagi K, Tokuzawa Y, et al. miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem Biophys Res Commun, 2008, 368(2): 267-272.
13. Zhang J, Li Z, Wang H, et al. Ultrasensitive quantification of mature microRNAs by real-time PCR based on ligation of a ribonucleotide-modified DNA probe. Chem Commun (Camb), 2011, 47(33): 9465-9467.
14. Huang J, Zhao L, Xing L, et al. MicroRNA-204 regulates RUNX2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells, 2010, 28(2): 357-364.
15. Hassan MQ, Gordon JA, Beloti MM, et al. A network connecting RUNX2, SATB2, and the miR-23a~27a~24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci U S A, 2010, 107(46): 19879-19884.
16. Li Z, Hassan MQ, Volinia S, et al. A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A, 2008, 105(37): 13906-13911.
17. Hu R, Liu W, Li H, et al. A RUNX2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem, 2011, 286(14): 12328-12339.
18. Dobreva G, Chahrour M, Dautzenberg M, et al. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell, 2006, 125(5): 971-986.
19. Li H, Xie H, Liu W, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest, 2009, 119(12): 3666-3677.
20. Luzi E, Marini F, Sala SC, et al. Osteogenic differentiation of human adipose tissue-derived stem cells is modulated by the miR-26a targeting of the SMAD1 transcription factor. J Bone Miner Res, 2008, 23(2): 287-295.
21. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest, 2006, 116(5): 1202-1209.
22. Zhang J, Tu Q, Bonewald LF, et al. Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J Bone Miner Res, 2011, 26(8): 1953-1963.
23. Wang T, Xu Z. miR-27 promotes osteoblast differentiation by modulating Wnt signaling. Biochem Biophys Res Commun, 2010, 402(2): 186-189.
24. Kapinas K, Kessler CB, Delany AM. miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling. J Cell Biochem, 2009, 108(1): 216-224.
25. Case N, Ma M, Sen B, et al. Beta-catenin levels influence rapid mechanical responses in osteoblasts. J Biol Chem, 2008, 283(43): 29196-29205.
26. Itoh T, Nozawa Y, Akao Y. MicroRNA-141 and -200a are involved in bone morphogenetic protein-2-induced mouse pre-osteoblast differentiation by targeting distal-less homeobox 5. J Biol Chem, 2009, 284(29): 19272-19279.
27. Itoh T, Takeda S, Akao Y. MicroRNA-208 modulates BMP-2-stimulated mouse preosteoblast differentiation by directly targeting V-ets erythroblastosis virus E26 oncogene homolog 1. J Biol Chem, 2010, 285(36): 27745-27752.
28. Kahai S, Lee SC, Lee DY, et al. MicroRNA miR-378 regulates nephronectin expression modulating osteoblast differentiation by targeting GalNT-7. PLoS One, 2009, 4(10): e7535.
29. Inose H, Ochi H, Kimura A, et al. A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A, 2009, 106(49): 20794-20799.
30. Hashimoto Y, Akiyama Y, Otsubo T, et al. Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis. Carcinogenesis, 2010, 31(5): 777-784.
31. Eskildsen T, Taipaleenmäki H, Stenvang J, et al. MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci U S A, 2011, 108(15): 6139-6144.
32. Perinpanayagam H, Zaharias R, Stanford C, et al. Early cell adhesion events differ between osteoporotic and non-osteoporotic osteoblasts. J Orthop Res, 2001, 19(6): 993-1000.
33. Lei SF, Papasian CJ, Deng HW. Polymorphisms in predicted miRNA binding sites and osteoporosis. J Bone Miner Res, 2011, 26(1): 72-78.
34. Zhang JF, Fu WM, He ML, et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol Biol Cell, 2011, 22(21): 3955-3961.
35. Huang S, Wang S, Bian C, et al. Up-regulation of miR-22 promotes osteogenic differentiation and inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells by repressing HDAC6 Protein Expression. Stem Cells Dev, 2012. [Epub agead of print].
36. Dong S, Yang B, Guo H, et al. MicroRNAs regulate osteogenesis and chondrogenesis. Biochem Biophys Res Commun, 2012, 418(4): 587-591.
  1. 1. Tiscornia G, Izpisúa Belmonte JC. MicroRNAs in embryonic stem cell function and fate. Genes Dev, 2010, 24(24): 2732-2741.
  2. 2. Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell, 2008, 133(2): 217-222.
  3. 3. Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu Rev Cell Dev Biol, 2009, 25: 629-648.
  4. 4. Baek WY, Kim JE. Transcriptional regulation of bone formation. Front Biosci (Schol Ed), 2011, 3: 126-135.
  5. 5. Griffiths-Jones S, Saini HK, van Dongen S, et al. miRBase: tools for microRNA genomics. Nucleic Acids Res, 2008, 36(Database issue): D154-158.
  6. 6. Komori T. Signaling networks in RUNX2-dependent bone development. J Cell Biochem, 2011, 112(3): 750-755.
  7. 7. Chen Y, Alman BA. Wnt pathway, an essential role in bone regeneration. J Cell Biochem, 2009, 106(3): 353-362.
  8. 8. Jiménez MJ, Balbín M, López JM, et al. Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Mol Cell Biol, 1999, 19(6): 4431-4442.
  9. 9. Thirunavukkarasu K, Halladay DL, Miles RR, et al. The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function. J Biol Chem, 2000, 275(33): 25163-25172.
  10. 10. Oskowitz AZ, Lu J, Penfornis P, et al. Human multipotent stromal cells from bone marrow and microRNA: regulation of differentiation and leukemia inhibitory factor expression. Proc Natl Acad Sci U S A, 2008, 105(47): 18372-18377.
  11. 11. Gaur T, Hussain S, Mudhasani R, et al. Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse. Dev Biol, 2010, 340(1): 10-21.
  12. 12. Mizuno Y, Yagi K, Tokuzawa Y, et al. miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem Biophys Res Commun, 2008, 368(2): 267-272.
  13. 13. Zhang J, Li Z, Wang H, et al. Ultrasensitive quantification of mature microRNAs by real-time PCR based on ligation of a ribonucleotide-modified DNA probe. Chem Commun (Camb), 2011, 47(33): 9465-9467.
  14. 14. Huang J, Zhao L, Xing L, et al. MicroRNA-204 regulates RUNX2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells, 2010, 28(2): 357-364.
  15. 15. Hassan MQ, Gordon JA, Beloti MM, et al. A network connecting RUNX2, SATB2, and the miR-23a~27a~24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci U S A, 2010, 107(46): 19879-19884.
  16. 16. Li Z, Hassan MQ, Volinia S, et al. A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A, 2008, 105(37): 13906-13911.
  17. 17. Hu R, Liu W, Li H, et al. A RUNX2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem, 2011, 286(14): 12328-12339.
  18. 18. Dobreva G, Chahrour M, Dautzenberg M, et al. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell, 2006, 125(5): 971-986.
  19. 19. Li H, Xie H, Liu W, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest, 2009, 119(12): 3666-3677.
  20. 20. Luzi E, Marini F, Sala SC, et al. Osteogenic differentiation of human adipose tissue-derived stem cells is modulated by the miR-26a targeting of the SMAD1 transcription factor. J Bone Miner Res, 2008, 23(2): 287-295.
  21. 21. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest, 2006, 116(5): 1202-1209.
  22. 22. Zhang J, Tu Q, Bonewald LF, et al. Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J Bone Miner Res, 2011, 26(8): 1953-1963.
  23. 23. Wang T, Xu Z. miR-27 promotes osteoblast differentiation by modulating Wnt signaling. Biochem Biophys Res Commun, 2010, 402(2): 186-189.
  24. 24. Kapinas K, Kessler CB, Delany AM. miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling. J Cell Biochem, 2009, 108(1): 216-224.
  25. 25. Case N, Ma M, Sen B, et al. Beta-catenin levels influence rapid mechanical responses in osteoblasts. J Biol Chem, 2008, 283(43): 29196-29205.
  26. 26. Itoh T, Nozawa Y, Akao Y. MicroRNA-141 and -200a are involved in bone morphogenetic protein-2-induced mouse pre-osteoblast differentiation by targeting distal-less homeobox 5. J Biol Chem, 2009, 284(29): 19272-19279.
  27. 27. Itoh T, Takeda S, Akao Y. MicroRNA-208 modulates BMP-2-stimulated mouse preosteoblast differentiation by directly targeting V-ets erythroblastosis virus E26 oncogene homolog 1. J Biol Chem, 2010, 285(36): 27745-27752.
  28. 28. Kahai S, Lee SC, Lee DY, et al. MicroRNA miR-378 regulates nephronectin expression modulating osteoblast differentiation by targeting GalNT-7. PLoS One, 2009, 4(10): e7535.
  29. 29. Inose H, Ochi H, Kimura A, et al. A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A, 2009, 106(49): 20794-20799.
  30. 30. Hashimoto Y, Akiyama Y, Otsubo T, et al. Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis. Carcinogenesis, 2010, 31(5): 777-784.
  31. 31. Eskildsen T, Taipaleenmäki H, Stenvang J, et al. MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. Proc Natl Acad Sci U S A, 2011, 108(15): 6139-6144.
  32. 32. Perinpanayagam H, Zaharias R, Stanford C, et al. Early cell adhesion events differ between osteoporotic and non-osteoporotic osteoblasts. J Orthop Res, 2001, 19(6): 993-1000.
  33. 33. Lei SF, Papasian CJ, Deng HW. Polymorphisms in predicted miRNA binding sites and osteoporosis. J Bone Miner Res, 2011, 26(1): 72-78.
  34. 34. Zhang JF, Fu WM, He ML, et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol Biol Cell, 2011, 22(21): 3955-3961.
  35. 35. Huang S, Wang S, Bian C, et al. Up-regulation of miR-22 promotes osteogenic differentiation and inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells by repressing HDAC6 Protein Expression. Stem Cells Dev, 2012. [Epub agead of print].
  36. 36. Dong S, Yang B, Guo H, et al. MicroRNAs regulate osteogenesis and chondrogenesis. Biochem Biophys Res Commun, 2012, 418(4): 587-591.