異位骨化發病機制的探討和研究策略_《華西醫學》

作者：

楊進 ,  孔清泉

四川大學華西醫院骨科（成都，610041）;

關鍵詞：

異位骨化發病機制 BMP 轉錄因子微小RNA

DOI：

10.7507/1002-0179.20130568

視頻：

導出 下載 收藏 掃碼 引用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

目的　探討異位骨化（HO）發病機制以及其研究策略。方法　查閱近年有關HO危險因素及發病機制的文獻，結合相關領域的方法學及新技術和新觀點進展綜合分析。結果　HO發病機制尚未完全明確，但其本質是一種體內互轉化現象。BMP-Smad、Wnt-beta-catenin和LIF -STAT3信號通路被認為是胚胎干細胞保持自我更新和向特定細胞定向分化過程中的中樞調控因子。TGFβ/BMP-Smad信號通路是干細胞定向分化成肌腱（韌帶）細胞的前提，是必要條件，但不是充分條件。微小RNA（miRNA）和TGFβ/BMP-Smad信號通路可以聯合作用，組合成不同的密碼來裁定細胞的命運和表型。結論　miRNAs和TGFβ/BMP-Smad信號通路可能是決定干細胞向肌腱細胞，或軟骨細胞，或肌腱和軟骨細胞混合成分哪一個方向分化的關鍵調控因素。通過對比分析干細胞在上述3種分化途徑中基因表達調控、蛋白結構和功能的差異，可能幫助我們尋找到決定肌腱細胞與軟骨細胞互相轉化分化的關鍵miRNAs，肌腱細胞定向分化的關鍵調控基因，以及揭開精確調控細胞分化方向的關鍵機制和調控網絡。

引用本文： 楊進,孔清泉. 異位骨化發病機制的探討和研究策略. 華西醫學, 2013, 28(11): 1791-1795. doi: 10.7507/1002-0179.20130568 復制

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2.	Doss MX, Chen S, Winkler J, et al. Transcriptomic and phenotypic analysis of murine embryonic stem cell derived BMP2+ lineage cells: an insight into mesodermal patterning[J]. Genome Biol, 2007, 8(9): R184.
3.	Paik S, Jung HS, Lee S. miR-449a regulates the chondrogenesis of human mesenchymal stem cells through direct targeting of lymphoid enhancer-binding factor-1[J]. Stem Cells Dev, 2012, 21(18): 3298-3308.
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12.	Mallanna SK, Rizzino A. Emergingroles of microRNAs in the control of embryonic stem cells and the genera-tion of induced pluripotent stem cells[J]. DevBiol, 2010, 344: 16-25.
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14.	Guo H, Ingolia NT, Weissman JS. Mammalian microRNAs predominantly act to decrease target mRNA levels[J]. Nature, 2010, 466(7308): 835-840.
15.	Suomi S, Taipaleenmaki H, Seppanen A, et al. MicroRNAs regulate osteogenesis and chondrogenesis of mouse bone marrow stromal cells[J]. Gene Regul Syst Bio, 2008, 22(2): 177-191.
16.	Kobayashi T, Lu J, Cobb BS, et al. Dicer-dependent pathways regulate chondrocyte proliferation and differentiation[J]. Proc Natl Acad Sci USA, 2008, 105(6): 1949-1954.
17.	Fei T, Xia K, Li Z, et al. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination[J]. Genome Res, 2010, 20(1): 36-44.
18.	Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation[J]. Cell Res, 2009, 19(1): 103-115.
19.	Tagliafico E, Brunelli S, Bergamaschi A, et al. TGFbeta/BMP activate the smooth muscle/bone differentiation programs in mesoangioblasts[J]. J Cell Sci, 2004, 117: 4377-4388.
20.	Nojima J, Kanomata K, Takada Y, et al. Dual roles of smad proteins in the conversion from myoblasts to osteoblastic cells by bone morphogenetic proteins[J]. J Biol Chem, 2010, 285(20): 15577-15586.
21.	Pryce BA, Watson SS, Murchison ND, et al. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation[J]. Development, 2009, 136(8): 1351-1361.
22.	Hoffmann A, Pelled G, Turgeman G, et al. Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells[J]. J Clin Invest, 2006, 116(4): 940-952.
23.	Retting KN, Song B, Yoon BS, et al. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation[J]. Development, 2009, 136(7): 1093-1104.
24.	Keller B, Yang T, Chen Y, et al. Interaction of TGFbeta and BMP signaling pathways during chondrogenesis[J]. PLoS One, 2011, 6(1): e16421.
25.	D‘Souza D, Patel K.Involvement of long- and short-range signalling during early tendon development[J]. Anat Embryol(Berl), 1999, 200(4): 367-375.
26.	Song B, Estrada KD, Lyons KM. Smad signaling in skeletal development and regeneration[J]. Cytokine Growth Factor Rev, 2009, 20(5-6): 379-388.
27.	Hellingman CA, Davidson EN, Koevoet W, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of smad1/5/8p prevents terminal differentiation and calcification[J]. Tissue Eng Part A, 2011, 17(7-8): 1157-1167.
28.	Hata A, Davis BN. Control of microRNA biogenesis by TGFbeta signaling pathway-A novel role of Smads in the nucleus[J]. Cytokine Growth Factor Rev, 2009, 20(5-6): 517-521.
29.	Liu Z, Shi W, Ji X, et al. Molecules mimicking Smad1 interacting with Hox stimulate bone formation[J]. J Biol Chem, 2004, 279(12): 11313-11319.
30.	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]. J Bone Miner Res, 2008, 23(2): 287-295.
31.	Lin EA, Kong L, Bai XH, et al. miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1[J]. J Biol Chem, 2009, 284(17): 11326-11335.
32.	Kim YJ, Hwang SJ, Bae YC, et al. MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue[J]. Stem Cells, 2009, 27(12): 3093-3102.
33.	Rogler CE, Levoci L, Ader T, et al. MicroRNA-23b cluster microRNAs regulate transforming growth factor-beta/bone morphogenetic protein signaling and liver stem cell differentiation by targeting Smads[J]. Hepatology, 2009, 50(2): 575-584.

1. 　Chalmers J, Gray DH, Rush J. Observation on the induction of bone in soft tissues[J]. J Bone Joint Surg (Br), 1975, 57(1): 36-45.
2. 　Doss MX, Chen S, Winkler J, et al. Transcriptomic and phenotypic analysis of murine embryonic stem cell derived BMP2+ lineage cells: an insight into mesodermal patterning[J]. Genome Biol, 2007, 8(9): R184.
3. 　Paik S, Jung HS, Lee S. miR-449a regulates the chondrogenesis of human mesenchymal stem cells through direct targeting of lymphoid enhancer-binding factor-1[J]. Stem Cells Dev, 2012, 21(18): 3298-3308.
4. 　Lorda-Diez CI, Montero JA, Martinez-Cue C. Transforming growth factors beta coordinate cartilage and tendon differentiation in the developing limb mesenchyme[J]. J Biol Chem 2009, 284(43): 29988-29996.
5. 　Bi Y, Ehirchiou D, Kilts TM, et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche[J]. Nat Med, 2007, 13(10): 1219-1227.
6. 　Wolfman NM, Hattersley G, Cox K, et al. Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family[J]. J Clin Invest, 1997, 100(2): 321-330.
7. 　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[J]. Proc Natl Acad Sci USA, 2010, 107(46): 19879-19884.
8. 　Moon SH, Park SR, Kim H, et al. Biological modification of ligamentum flavum cells by marker gene transfer and recombinant human bone morphogenetic protein-2[J]. Spine(Phila Pa 1976), 2004, 29(9): 960-965.
9. 　Tsukamoto N, Maeda T, Miura H, et al. Repetitive tensile stress to rat caudal vertebrae inducing cartilage formation in the spinal ligaments: a possible role of mechanical stress in the development of ossification of the spinal ligaments[J]. J Neurosurg Spine, 2006, 5(3): 234-242.
10. 　Bobacz K, UIIrich R, Amoyo L, et al. Stimulatory effects of distinct members of the bone morphogenetic protein family on ligament fibroblasts [J]. Ann Rheum Dis, 2006, 65(2): 169-177.
11. 　Kishiya M, Sawada T, Kanemaru K, et al. A functional RNAi screen for Runx-2regulated genes associated with ectopic bone formation in human spinal ligaments[J]. J Pharmacol Sci, 2008, 106(3): 404-414.
12. 　Mallanna SK, Rizzino A. Emergingroles of microRNAs in the control of embryonic stem cells and the genera-tion of induced pluripotent stem cells[J]. DevBiol, 2010, 344: 16-25.
13. 　Martinez NJ, Gregory RI. MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity[J]. Cell Stem Cell, 2010, 7(1): 31-35.
14. 　Guo H, Ingolia NT, Weissman JS. Mammalian microRNAs predominantly act to decrease target mRNA levels[J]. Nature, 2010, 466(7308): 835-840.
15. 　Suomi S, Taipaleenmaki H, Seppanen A, et al. MicroRNAs regulate osteogenesis and chondrogenesis of mouse bone marrow stromal cells[J]. Gene Regul Syst Bio, 2008, 22(2): 177-191.
16. 　Kobayashi T, Lu J, Cobb BS, et al. Dicer-dependent pathways regulate chondrocyte proliferation and differentiation[J]. Proc Natl Acad Sci USA, 2008, 105(6): 1949-1954.
17. 　Fei T, Xia K, Li Z, et al. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination[J]. Genome Res, 2010, 20(1): 36-44.
18. 　Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation[J]. Cell Res, 2009, 19(1): 103-115.
19. 　Tagliafico E, Brunelli S, Bergamaschi A, et al. TGFbeta/BMP activate the smooth muscle/bone differentiation programs in mesoangioblasts[J]. J Cell Sci, 2004, 117: 4377-4388.
20. 　Nojima J, Kanomata K, Takada Y, et al. Dual roles of smad proteins in the conversion from myoblasts to osteoblastic cells by bone morphogenetic proteins[J]. J Biol Chem, 2010, 285(20): 15577-15586.
21. 　Pryce BA, Watson SS, Murchison ND, et al. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation[J]. Development, 2009, 136(8): 1351-1361.
22. 　Hoffmann A, Pelled G, Turgeman G, et al. Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells[J]. J Clin Invest, 2006, 116(4): 940-952.
23. 　Retting KN, Song B, Yoon BS, et al. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation[J]. Development, 2009, 136(7): 1093-1104.
24. 　Keller B, Yang T, Chen Y, et al. Interaction of TGFbeta and BMP signaling pathways during chondrogenesis[J]. PLoS One, 2011, 6(1): e16421.
25. 　D‘Souza D, Patel K.Involvement of long- and short-range signalling during early tendon development[J]. Anat Embryol(Berl), 1999, 200(4): 367-375.
26. 　Song B, Estrada KD, Lyons KM. Smad signaling in skeletal development and regeneration[J]. Cytokine Growth Factor Rev, 2009, 20(5-6): 379-388.
27. 　Hellingman CA, Davidson EN, Koevoet W, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of smad1/5/8p prevents terminal differentiation and calcification[J]. Tissue Eng Part A, 2011, 17(7-8): 1157-1167.
28. 　Hata A, Davis BN. Control of microRNA biogenesis by TGFbeta signaling pathway-A novel role of Smads in the nucleus[J]. Cytokine Growth Factor Rev, 2009, 20(5-6): 517-521.
29. 　Liu Z, Shi W, Ji X, et al. Molecules mimicking Smad1 interacting with Hox stimulate bone formation[J]. J Biol Chem, 2004, 279(12): 11313-11319.
30. 　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]. J Bone Miner Res, 2008, 23(2): 287-295.
31. 　Lin EA, Kong L, Bai XH, et al. miR-199a, a bone morphogenic protein 2-responsive MicroRNA, regulates chondrogenesis via direct targeting to Smad1[J]. J Biol Chem, 2009, 284(17): 11326-11335.
32. 　Kim YJ, Hwang SJ, Bae YC, et al. MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue[J]. Stem Cells, 2009, 27(12): 3093-3102.
33. 　Rogler CE, Levoci L, Ader T, et al. MicroRNA-23b cluster microRNAs regulate transforming growth factor-beta/bone morphogenetic protein signaling and liver stem cell differentiation by targeting Smads[J]. Hepatology, 2009, 50(2): 575-584.

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異位骨化發病機制的探討和研究策略

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《華西醫學》

異位骨化發病機制的探討和研究策略

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