异位骨化发病机制的探讨和研究策略_West China Medical Journal

Authors：

杨进 ,  孔清泉

Corresponding author：

孔清泉, Email: yangjin19790801@sina.cn

Keywords：

异位骨化; 发病机制; BMP 转录因子; 微小RNA

DOI：

10.7507/1002-0179.20130568

Video：

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目的　探讨异位骨化（HO）发病机制以及其研究策略。方法　查阅近年有关HO危险因素及发病机制的文献，结合相关领域的方法学及新技术和新观点进展综合分析。结果　HO发病机制尚未完全明确，但其本质是一种体内互转化现象。BMP-Smad、Wnt-beta-catenin和LIF -STAT3信号通路被认为是胚胎干细胞保持自我更新和向特定细胞定向分化过程中的中枢调控因子。TGFβ/BMP-Smad信号通路是干细胞定向分化成肌腱（韧带）细胞的前提，是必要条件，但不是充分条件。微小RNA（miRNA）和TGFβ/BMP-Smad信号通路可以联合作用，组合成不同的密码来裁定细胞的命运和表型。结论　miRNAs和TGFβ/BMP-Smad信号通路可能是决定干细胞向肌腱细胞，或软骨细胞，或肌腱和软骨细胞混合成分哪一个方向分化的关键调控因素。通过对比分析干细胞在上述3种分化途径中基因表达调控、蛋白结构和功能的差异，可能帮助我们寻找到决定肌腱细胞与软骨细胞互相转化分化的关键miRNAs，肌腱细胞定向分化的关键调控基因，以及揭开精确调控细胞分化方向的关键机制和调控网络。

Citation： 杨进,孔清泉. 异位骨化发病机制的探讨和研究策略. West China Medical Journal, 2013, 28(11): 1791-1795. doi: 10.7507/1002-0179.20130568 Copy

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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.
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.
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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.

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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异位骨化发病机制的探讨和研究策略

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