ADVANCES IN OSTEOGENIC MECHANISM AND OSTEOGENIC EFFECTS OF BONE MORPHOGENETIC PROTEIN 6_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

XU Gang , ZHANG Changchun , ZHOU Jiansheng , HUANG Zhen , MENG Hongya.

Department of Orthopaedics, the First Affiliated Hospital of Bengbu Medical College, Bengbu Anhui, 233004, P.R.China. Corresponding author: ZHANG Changchun, E-mail: zccanhui@sina.com;

Corresponding author：

Keywords：

Bone morphogenetic protein 6; Osteogenic mechanism; Osteogenic effect

DOI：

10.7507/1002-1892.20130249

Video：

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Objective To review the osteogenic mechanism and osteogenic effects of bone morphogenetic protein 6 (BMP-6) so as to provide the basis for further research of BMP-6. Methods The related articles about the osteogenic mechanism and the osteogenic effects of BMP-6 in experimental animals were extensively summarized. Results BMP-6 from bone matrix can transduct the osteogenic signal to bone marrow mesenchymal stem cells (BMSCs) by means of Smad protein signal transduction pathway. And the BMSCs which received the signals will differentiate into osteoblasts and chondroblasts. Therefore, BMP-6 plays an important role in the development and maturation of bone and cartilage. In addition, BMP-6 has a close relation with bone diseases, such as fracture, osteoporosis, and bone tumor. Conclusion The deep research of BMP-6 is expected to provide a new therapeutic approach for treating bone diseases of nonunion, osteoarthritis, and osteoporosis.

Citation： XU Gang,ZHANG Changchun,ZHOU Jiansheng,HUANG Zhen,MENG Hongya.. ADVANCES IN OSTEOGENIC MECHANISM AND OSTEOGENIC EFFECTS OF BONE MORPHOGENETIC PROTEIN 6. Chinese Journal of Reparative and Reconstructive Surgery, 2013, 27(9): 1144-1147. doi: 10.7507/1002-1892.20130249 Copy

1.	Moghaddam A, Elleser C, Biglari B, et al. Clinical application of BMP-7 in long bone non-unions. Arch Orthop Trauma Surg, 2010, 130(1): 71-76.
2.	Li JZ, Li H, Sasaki T, et al. Osteogenic potential of five different recombinant human bone morphogenetic protein adenoviral vectors in the rat. Gene Ther, 2003, 10(20): 1735-1743.
3.	何焕玲, 李星星, 赖天霞, 等. BMP-2、-3、-6和-12在骨肉瘤细胞株中的表达. 中国组织化学与细胞化学杂志, 2007, 16(2): 134-137.
4.	Goumans MJ, Mummery C. Functional anaysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol, 2000, 44(3): 253-265.
5.	Vukicevic S, Grgurevic L. BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev, 2009, 20(5-6): 441-448.
6.	Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors, 2004, 22(4): 233-241.
7.	程宗生, 关键. 骨形态发生蛋白/Smad信号转导机制及其对离心力刺激的响应. 国际口腔医学杂志, 2009, 36(3): 335-337.
8.	杨尊. 低强度脉冲超声波对人类牙周膜细胞骨形成蛋白BMP成骨调控机制的初步研究. 重庆: 重庆医科大学, 2011.
9.	Sheu SY, Tsai CC, Sun JS, et al. Stimulatory effect of puerarin on bone formation through co-activation of nitric oxide and bone morphogenetic protein-2/mitogen-activated protein kinases pathways in mice. Chin Med J, 2012, 125(20): 3646-3653.
10.	Li C, Yang X, He Y, et al. Bone morphogenetic protein-9 induces osteogenic differentiation of rat dental follicle stem cells in P38 and ERK1/2 MAPK dependent manner. Int J Med Sci, 2012, 9(10): 862-871.
11.	Seamon J, Wang X, Cui F, et al. Adenoviral delivery of the VEGF and BMP-6 genes to rat mesenchymal stem cells potentiates osteogenesis. Bone Marrow Res, 2013, 2013: 737580.
12.	Mizrahi O, Shevn D, Tawackoli W, et al. BMP-6 is more efficient in bone formation than BMP-2 when overexpressed in mesenchymal stem cells. Gene Ther, 2013, 20(4): 370-377.
13.	Visser R, Pilar M, Santos-Ruiz L, et al. Basic fibroblast factor enhances the osteogenic differentiation induced by bone morphogenetic protein-6 in vitro and in vivo. Cytokine, 2012, 58(1): 27-33.
14.	Zachos TA, Shiekls KM, Bertone AL. Gene-mediated oeteogenic differentiation of stem cells by bone morphogentic proteins-2 or -6. J Orthop Res, 2006, 24(6): 1279-1291.
15.	Sheyn D, Kallai L, Tawackoli W, et al. Gene-modified adult stem cells regenerate vertebral bone defect in a rat model. Mol Pharm, 2011, 8(5): 1592-1601.
16.	Perry MJ, Mc Dougall KE, Hou SC, et al. Impaired growth plate fuction in bmp-6 null mice. Bone, 2008, 42(1): 216-225.
17.	Choi S, Cho TJ, Kwon SK, et al. Chondrogenesis of periodontal ligament stem cells by transforming growth factor-β3 and bone morphogenetic protein-6 in a normal healthy impacted third molar. Int J Oral Sci, 2013, 5(1): 7-13.
18.	Kayabaşi GK, Aydin RS, Gümüşderelioğlu M. In vitro chondrogenesis by BMP6 gene therapy. J Biomed Mater Res A, 2012, 101(5): 1353-1361.
19.	de Mara CS, Duarte AS, Sartori-Cintra AR, et al. Chondrogenesisi from umbilical cord blood cells stimulated with BMP-2 and BMP-6. Rheumatol Int, 2013, 33(1): 121-128.
20.	Nilsson O, Parker EA, Hegde A, et al. Gradients in bone morphogenetic protein-related gene expression across the growth plate. J Endocrinol, 2007, 193(1): 75-84.
21.	Menendez MI, Clark DJ, Carlton M, et al. Direct delayed human adnoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. Osteoarthritis Cartilage, 2011, 19(8): 1066-1075.
22.	Fischerauer EE, Manninger M, Seles M, et al. BMP-6 and BMPR-1a are up-regulateded in the growth plate of the fractured tibia. J Orthop Res, 2013, 31(3): 357-363.
23.	Kemmis CM, Vahdati A, Weiss HE, et al. Bone morphogenetic protein 6 drives both osteogenesis and chondrogenesis in murine adipose-derived mesenchymal cells depending on culture conditions. Biochem Biophys Res Commun, 2010, 401(1): 20-25.
24.	Song K, Krause C, Shi S, et al. Identification of a key residue mediating bone morphogenetic protein (BMP)-6 resistance to noggin inhibition allows for engineered BMPs with superior agonist activity. J Biol Chem, 2010, 285(16): 12169-12180.
25.	Sinic P, Culej JB, Orlic I, et al. Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem, 2006, 281(35): 25509-25521.
26.	尚德阳. 肾虚骨质疏松症大鼠骨、肾、下丘脑组织BMP6/BMP7、Smurf1/Smurf2的mRNA及其蛋白表达的实验研究. 沈阳: 辽宁中医药大学, 2008.
27.	Brkljacic J, Pauk M, et al. Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity. Int Orthop, 2013, 37(3): 529-541.
28.	Hashida Y, Nemoto Y, Imajoh M, et al. Promoter methylation of the bone morphogenetic protein 6 gene in multiple myeloma. Oncol Rep, 2012, 27(3): 825-830.
29.	Yuen HF, McCrudden CM, Grills C, et al. Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression. Cancer Sci, 2012, 103(6): 1145-1154.

1. Moghaddam A, Elleser C, Biglari B, et al. Clinical application of BMP-7 in long bone non-unions. Arch Orthop Trauma Surg, 2010, 130(1): 71-76.
2. Li JZ, Li H, Sasaki T, et al. Osteogenic potential of five different recombinant human bone morphogenetic protein adenoviral vectors in the rat. Gene Ther, 2003, 10(20): 1735-1743.
3. 何焕玲, 李星星, 赖天霞, 等. BMP-2、-3、-6和-12在骨肉瘤细胞株中的表达. 中国组织化学与细胞化学杂志, 2007, 16(2): 134-137.
4. Goumans MJ, Mummery C. Functional anaysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol, 2000, 44(3): 253-265.
5. Vukicevic S, Grgurevic L. BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev, 2009, 20(5-6): 441-448.
6. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors, 2004, 22(4): 233-241.
7. 程宗生, 关键. 骨形态发生蛋白/Smad信号转导机制及其对离心力刺激的响应. 国际口腔医学杂志, 2009, 36(3): 335-337.
8. 杨尊. 低强度脉冲超声波对人类牙周膜细胞骨形成蛋白BMP成骨调控机制的初步研究. 重庆: 重庆医科大学, 2011.
9. Sheu SY, Tsai CC, Sun JS, et al. Stimulatory effect of puerarin on bone formation through co-activation of nitric oxide and bone morphogenetic protein-2/mitogen-activated protein kinases pathways in mice. Chin Med J, 2012, 125(20): 3646-3653.
10. Li C, Yang X, He Y, et al. Bone morphogenetic protein-9 induces osteogenic differentiation of rat dental follicle stem cells in P38 and ERK1/2 MAPK dependent manner. Int J Med Sci, 2012, 9(10): 862-871.
11. Seamon J, Wang X, Cui F, et al. Adenoviral delivery of the VEGF and BMP-6 genes to rat mesenchymal stem cells potentiates osteogenesis. Bone Marrow Res, 2013, 2013: 737580.
12. Mizrahi O, Shevn D, Tawackoli W, et al. BMP-6 is more efficient in bone formation than BMP-2 when overexpressed in mesenchymal stem cells. Gene Ther, 2013, 20(4): 370-377.
13. Visser R, Pilar M, Santos-Ruiz L, et al. Basic fibroblast factor enhances the osteogenic differentiation induced by bone morphogenetic protein-6 in vitro and in vivo. Cytokine, 2012, 58(1): 27-33.
14. Zachos TA, Shiekls KM, Bertone AL. Gene-mediated oeteogenic differentiation of stem cells by bone morphogentic proteins-2 or -6. J Orthop Res, 2006, 24(6): 1279-1291.
15. Sheyn D, Kallai L, Tawackoli W, et al. Gene-modified adult stem cells regenerate vertebral bone defect in a rat model. Mol Pharm, 2011, 8(5): 1592-1601.
16. Perry MJ, Mc Dougall KE, Hou SC, et al. Impaired growth plate fuction in bmp-6 null mice. Bone, 2008, 42(1): 216-225.
17. Choi S, Cho TJ, Kwon SK, et al. Chondrogenesis of periodontal ligament stem cells by transforming growth factor-β3 and bone morphogenetic protein-6 in a normal healthy impacted third molar. Int J Oral Sci, 2013, 5(1): 7-13.
18. Kayabaşi GK, Aydin RS, Gümüşderelioğlu M. In vitro chondrogenesis by BMP6 gene therapy. J Biomed Mater Res A, 2012, 101(5): 1353-1361.
19. de Mara CS, Duarte AS, Sartori-Cintra AR, et al. Chondrogenesisi from umbilical cord blood cells stimulated with BMP-2 and BMP-6. Rheumatol Int, 2013, 33(1): 121-128.
20. Nilsson O, Parker EA, Hegde A, et al. Gradients in bone morphogenetic protein-related gene expression across the growth plate. J Endocrinol, 2007, 193(1): 75-84.
21. Menendez MI, Clark DJ, Carlton M, et al. Direct delayed human adnoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. Osteoarthritis Cartilage, 2011, 19(8): 1066-1075.
22. Fischerauer EE, Manninger M, Seles M, et al. BMP-6 and BMPR-1a are up-regulateded in the growth plate of the fractured tibia. J Orthop Res, 2013, 31(3): 357-363.
23. Kemmis CM, Vahdati A, Weiss HE, et al. Bone morphogenetic protein 6 drives both osteogenesis and chondrogenesis in murine adipose-derived mesenchymal cells depending on culture conditions. Biochem Biophys Res Commun, 2010, 401(1): 20-25.
24. Song K, Krause C, Shi S, et al. Identification of a key residue mediating bone morphogenetic protein (BMP)-6 resistance to noggin inhibition allows for engineered BMPs with superior agonist activity. J Biol Chem, 2010, 285(16): 12169-12180.
25. Sinic P, Culej JB, Orlic I, et al. Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem, 2006, 281(35): 25509-25521.
26. 尚德阳. 肾虚骨质疏松症大鼠骨、肾、下丘脑组织BMP6/BMP7、Smurf1/Smurf2的mRNA及其蛋白表达的实验研究. 沈阳: 辽宁中医药大学, 2008.
27. Brkljacic J, Pauk M, et al. Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity. Int Orthop, 2013, 37(3): 529-541.
28. Hashida Y, Nemoto Y, Imajoh M, et al. Promoter methylation of the bone morphogenetic protein 6 gene in multiple myeloma. Oncol Rep, 2012, 27(3): 825-830.
29. Yuen HF, McCrudden CM, Grills C, et al. Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression. Cancer Sci, 2012, 103(6): 1145-1154.

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Chinese Journal of Reparative and Reconstructive Surgery

ADVANCES IN OSTEOGENIC MECHANISM AND OSTEOGENIC EFFECTS OF BONE MORPHOGENETIC PROTEIN 6

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