Research progress in osteogenesis and osteogenic mechanism of heparan sulfate_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

XU Zhujie ¹ , CHEN Jinghua ² , SHAO Wei ¹ , WANG Rui ¹ ,  LIU Yi ^1,2

1. Department of Orthopedics, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi Jiangsu, 214000, P.R.China;
2. Medicinal Biopolymer Laboratory of College of Pharmacy, Jiangnan University, Wuxi Jiangsu, 214000, P.R.China;

Corresponding author：

LIU Yi, Email: wxryliuyi@126.com

Keywords：

Heparan sulfate; bone defect repair; osteogenesis; osteogenic mechanism; signaling pathway

DOI：

10.7507/1002-1892.201701103

Video：

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Objective To discuss the role of heparan sulfate (HS) in bone formation and bone remodeling and summarize the research progress in the osteogenic mechanism of HS. Methods The domestic and abroad related literature about HS acting on osteoblast cell line in vitro, HS and HS composite scaffold materials acting on the ani-mal bone defect models, and the effect of HS proteoglycans on bone development were summarized and analyzed. Results Many growth factors involved in fracture healing especially heparin-binding growth factors, such as fibroblast growth factors, bone morphogenetic protein, and transforming growth factor β, are connected noncovalently with long HS chains. HS proteoglycans protect these proteins from protease degradation and are directly involved in the regulation of growth factors signaling and bone cell function. HS can promote the differentiation of stem cells into osteoblasts and enhance the differentiation of osteoblasts. In bone matrix, HS plays a significant role in promoting the formation, maintaining the stability, and accelerating the mineralization. Conclusion The osteogenesis of HS is pronounced. HS is likely to become the clinical treatment measures of fracture nonunion or delayed union, and is expected to provide more choices for bone tissue engineering with identification of its long-term safety.

Citation： XU Zhujie, CHEN Jinghua, SHAO Wei, WANG Rui, LIU Yi. Research progress in osteogenesis and osteogenic mechanism of heparan sulfate. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(8): 1016-1020. doi: 10.7507/1002-1892.201701103 Copy

1.	Song SJ, Hutmacher D, Nurcombe V, et al. Temporal expression of proteoglycans in the rat limb during bone healing. Gene, 2006, 379: 92-100.
2.	Fu L, Suflita M, Linhardt RJ. Bioengineered heparins and heparan sulfates. Adv Drug Deliv Rev, 2016, 97: 237-249.
3.	Schultz V, Suflita M, Liu X, et al. Heparan sulfate domains required for fibroblast growth factor 1 and 2 signaling through fibroblast growth factor receptor 1c. J Biol Chem, 2017, 292(6): 2495-2509.
4.	Esko JD, Selleck SB. Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem, 2002, 71: 435-471.
5.	Rai B, Nurcombe V, Cool SM. Heparan sulfate-based treatments for regenerative medicine. Crit Rev Eukaryot Gene Expr, 2011, 21(1): 1-12.
6.	Zhang F, Sodroski C, Cha H, et al. Infection of hepatocytes with HCV increases cell surface levels of heparan sulfate proteoglycans, uptake of cholesterol and lipoprotein, and virus entry by up-regulating SMAD6 and SMAD7. Gastroenterology, 2017, 152(1): 257-270. e7.
7.	Onishi A, St Ange K, Dordick JS, et al. Heparin and anticoagulation. Front Biosci (Landmark Ed), 2016, 21: 1372-1392.
8.	Li JP, Kusche-Gullberg M. Heparan Sulfate: Biosynthesis, Structure, and Function. Int Rev Cell Mol Biol, 2016, 325: 215-273.
9.	Kamhi E, Joo EJ, Dordick JS, et al. Glycosaminoglycans in infectious disease. Biol Rev Camb Philos Soc, 2013, 88(4): 928-943.
10.	Zhang B, Xiao W, Qiu H, et al. Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia. J Clin Invest, 2014, 124(1): 209-221.
11.	Thompson WR, Modla S, Grindel BJ, et al. Perlecan/Hspg2 deficiency alters the pericellular space of the lacunocanalicular system surrounding osteocytic processes in cortical bone. J Bone Miner Res, 2011, 26(3): 618-629.
12.	Dombrowski C, Song SJ, Chuan P, et al. Heparan sulfate mediates the proliferation and differentiation of rat mesenchymal stem cells. Stem Cells Dev, 2009, 18(4): 661-670.
13.	Haupt LM, Murali S, Mun FK, et al. The heparan sulfate proteoglycan (HSPG) glypican-3 mediates commitment of MC3T3-E1 cells toward osteogenesis. J Cell Physiol, 2009, 220(3): 780-791.
14.	Moussa FM, Hisijara IA, Sondag GR, et al. Osteoactivin promotes osteoblast adhesion through HSPG and αvβ1 integrin. J Cell Biochem, 2014, 115(7): 1243-1253.
15.	Qin X, Jiang Q, Matsuo Y, et al. Cbfb regulates bone development by stabilizing Runx family proteins. J Bone Miner Res, 2015, 30(4): 706-714.
16.	Smith PN, Freeman C, Yu D, et al. Heparanase in primary human osteoblasts. J Othorp Res, 2010, 28(10): 1315-1322.
17.	Jackson RA, Murali S, van Wijnen AJ, et al. Heparan sulfate regulates the anabolic activity of MC3T3-E1 preosteoblast cells by induction of Runx2. J Cell Physiol, 2007, 210(1): 38-50.
18.	Manton KJ, Sadasivam M, Cool SM, et al. Bone-specific heparan sulfates induce osteoblast growth arrest and downregulation of retinoblastoma protein. J Cell Physiol, 2006, 209(1): 219-229.
19.	Ruan J, Trotter TN, Nan L, et al. Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease. Bone, 2013, 57(1): 10-17.
20.	Han Q, Liu F, Zhou Y. Increased expression of heparanase in osteogenic differentiation of rat marrow stromal cells. Exp Ther Med, 2013, 5(6): 1697-1700.
21.	Saijo M, Kitazawa R, Nakajima M, et al. Heparanase mRNA expression during fracture repair in mice. Histochem Cell Biol, 2003, 120(6): 493-503.
22.	Chuang CY, Lord MS, Melrose J, et al. Heparan sulfate dependent signaling of fibroblast growth factor (FGF) 18 by chondrocyte-derived perlecan. Biochemistry, 2010, 49(26): 5524-5532.
23.	Manton KJ, Leong DF, Cool SM, et al. Disruption of heparan and chondroitin sulfate signaling enhances mesenchymal stem cell-derived osteogenic differentiation via bone morphogenetic protein signaling pathways. Stem Cells, 2007, 25(11): 2845-2854.
24.	Genander M, Cook PJ, Ramsköld D, et al. BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages. Cell Stem Cell, 2014, 15(5): 619-633.
25.	Jackson RA, McDonald MM, Nurcombe V, et al. The use of heparan sulfate to augment fracture repair in a rat fracture model. J Orthop Res, 2006, 24(4): 636-644.
26.	Lafont J, Blanquaert F, Colombier ML, et al. Kinetic study of early regenerative effects of RGTA11, a heparan sulfate mimetic, in rat craniotomy defects. Calcif Tissue Int, 2004, 75(6): 517-525.
27.	Gdalevitch M, Kasaai B, Alam N, et al. The effect of heparan sulfate application on bone formation during distraction osteogenesis. PLoS One, 2013, 8(2): e56790.
28.	Woodruff MA, Rath SN, Susanto E, et al. Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model. J Mol Hist, 2007, 38(5): 425-433.
29.	Rai B, Chatterjea A, Lim ZX, et al. Repair of segmental ulna defects using a β-TCP implant in combination with a heparan sulfate glycosaminoglycan variant. Acta Biomater, 2015, 28: 193-204.
30.	Noble BS. The osteocyte lineage. Arch Biochem Biophys, 2008, 473(2): 106-111.
31.	Wang B, Lai X, Price C, et al. Perlecan-containing pericellular matrix regulates solute transport and mechanosensing within the osteocyte lacunar-canalicular system. J Bone Miner Res, 2014, 29(4): 878-891.
32.	Whitelock JM, Melrose J, Iozzo RV. Diverse cell signaling events modulated by perlecan. Biochemistry, 2008, 47(43): 11174-11183.
33.	Lowe DA, Lepori-Bui N, Fomin PV, et al. Deficiency in perlecan/HSPG2 during bone development enhances osteogenesis and decreases quality of adult bone in mice. Calcif Tissue Int, 2014, 95(1): 29-38.
34.	Ratzka A, Kalus I, Moser M, et al. Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. Dev Dyn, 2008, 237(2): 339-353.
35.	Jackson RA, Nurcombe V, Cool SM. Coordinated fibroblast growth factor and heparan sulfate regulation of osteogenesis. Gene, 2006, 379: 79-91.
36.	Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell, 2000, 103(2): 211-225.
37.	Ellman MB, Yan D, Ahmadinia K, et al. Fibroblast growth factor control of cartilage homeostasis. J Cell Biochem, 2013, 114(4): 735-742.
38.	Wu ZL, Zhang L, Yabe T, et al. The Involvement of Heparan Sulfate (HS) in FGF1/HS/FGFR1 Signaling Complex. J Biol Chem, 2003, 278(19): 17121-17129.
39.	Debiais F, Lemonnier J, Hay E, et al. Fibroblast growth factor-2 increases N-cadherin expression through protein kinase C and Src-kinase pathways in human calvaria osteoblasts. J Cell Biochem, 2001, 81(1): 68-81.
40.	Marie PJ. Fibroblast growth factor signaling controlling osteoblast differentiation. Gene, 2003, 316: 23-32.
41.	Kim HJ, Kim JH, Bae SC, et al. The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J Biol Chem, 2003, 278(1): 319-326.
42.	Mochly-Rosen D, Das K, Grimes KV. Protein kinase C, an elusive therapeutic target? Nat Rev Drug Discov, 2012, 11(12): 937-957.
43.	宋淑军, 张建中, 贾桂玥. 硫酸乙酰肝素通过 PKC 促进大鼠成骨细胞的增殖. 中国骨质疏松杂志, 2010, 16(5): 322-324.
44.	Wolski H, Drews K, Bogacz A, et al. The RANKL/RANK/OPG signal trail: significance of genetic polymorphisms in the etiology of postmenopausal osteoporosis. Ginekol Pol, 2016, 87(5): 347-352.
45.	Li M, Yang S, Xu D. Heparan sulfate regulates the structure and function of osteoprotegerin in osteoclastogenesis. J Biol Chem, 2016, 291(46): 24160-24171.
46.	Bastami F, Paknejad Z, Jafari M, et al. Fabrication of a three-dimensional β-tricalcium-phosphate/gelatin containing chitosan-based nanoparticles for sustained release of bone morphogenetic protein-2: Implication for bone tissue engineering. Mater Sci Eng C Mater Biol Appl, 2017, 72: 481-491.
47.	Bramono DS, Murali S, Rai B, et al. Bone marrow-derived heparan sulfate potentiates the osteogenic activity of bone morphogenetic protein-2 (BMP-2). Bone, 2012, 50(4): 954-964.
48.	Murali S, Rai B, Dombrowski C, et al. Affinity-selected heparan sulfate for bone repair. Biomaterials, 2013, 34(22): 5594-5605.
49.	Jiao X, Billings PC, O’Connell MP, et al. Heparan sulfate proteoglycans (HSPGs) modulate BMP2 osteogenic bioactivity in C2C12 cells. J Biol Chem, 2007, 282(2): 1080-1086.
50.	Baht GS, Silkstone D, Nadesan P, et al. Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation. J Orthop Res, 2014, 32(4): 581-586.
51.	Levi B, James AW, Nelson ER, et al. Role of Indian hedgehog signaling in palatal osteogenesis. Plast Reconstr Surg, 2011, 127(3): 1182-1190.

1. Song SJ, Hutmacher D, Nurcombe V, et al. Temporal expression of proteoglycans in the rat limb during bone healing. Gene, 2006, 379: 92-100.
2. Fu L, Suflita M, Linhardt RJ. Bioengineered heparins and heparan sulfates. Adv Drug Deliv Rev, 2016, 97: 237-249.
3. Schultz V, Suflita M, Liu X, et al. Heparan sulfate domains required for fibroblast growth factor 1 and 2 signaling through fibroblast growth factor receptor 1c. J Biol Chem, 2017, 292(6): 2495-2509.
4. Esko JD, Selleck SB. Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem, 2002, 71: 435-471.
5. Rai B, Nurcombe V, Cool SM. Heparan sulfate-based treatments for regenerative medicine. Crit Rev Eukaryot Gene Expr, 2011, 21(1): 1-12.
6. Zhang F, Sodroski C, Cha H, et al. Infection of hepatocytes with HCV increases cell surface levels of heparan sulfate proteoglycans, uptake of cholesterol and lipoprotein, and virus entry by up-regulating SMAD6 and SMAD7. Gastroenterology, 2017, 152(1): 257-270. e7.
7. Onishi A, St Ange K, Dordick JS, et al. Heparin and anticoagulation. Front Biosci (Landmark Ed), 2016, 21: 1372-1392.
8. Li JP, Kusche-Gullberg M. Heparan Sulfate: Biosynthesis, Structure, and Function. Int Rev Cell Mol Biol, 2016, 325: 215-273.
9. Kamhi E, Joo EJ, Dordick JS, et al. Glycosaminoglycans in infectious disease. Biol Rev Camb Philos Soc, 2013, 88(4): 928-943.
10. Zhang B, Xiao W, Qiu H, et al. Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia. J Clin Invest, 2014, 124(1): 209-221.
11. Thompson WR, Modla S, Grindel BJ, et al. Perlecan/Hspg2 deficiency alters the pericellular space of the lacunocanalicular system surrounding osteocytic processes in cortical bone. J Bone Miner Res, 2011, 26(3): 618-629.
12. Dombrowski C, Song SJ, Chuan P, et al. Heparan sulfate mediates the proliferation and differentiation of rat mesenchymal stem cells. Stem Cells Dev, 2009, 18(4): 661-670.
13. Haupt LM, Murali S, Mun FK, et al. The heparan sulfate proteoglycan (HSPG) glypican-3 mediates commitment of MC3T3-E1 cells toward osteogenesis. J Cell Physiol, 2009, 220(3): 780-791.
14. Moussa FM, Hisijara IA, Sondag GR, et al. Osteoactivin promotes osteoblast adhesion through HSPG and αvβ1 integrin. J Cell Biochem, 2014, 115(7): 1243-1253.
15. Qin X, Jiang Q, Matsuo Y, et al. Cbfb regulates bone development by stabilizing Runx family proteins. J Bone Miner Res, 2015, 30(4): 706-714.
16. Smith PN, Freeman C, Yu D, et al. Heparanase in primary human osteoblasts. J Othorp Res, 2010, 28(10): 1315-1322.
17. Jackson RA, Murali S, van Wijnen AJ, et al. Heparan sulfate regulates the anabolic activity of MC3T3-E1 preosteoblast cells by induction of Runx2. J Cell Physiol, 2007, 210(1): 38-50.
18. Manton KJ, Sadasivam M, Cool SM, et al. Bone-specific heparan sulfates induce osteoblast growth arrest and downregulation of retinoblastoma protein. J Cell Physiol, 2006, 209(1): 219-229.
19. Ruan J, Trotter TN, Nan L, et al. Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease. Bone, 2013, 57(1): 10-17.
20. Han Q, Liu F, Zhou Y. Increased expression of heparanase in osteogenic differentiation of rat marrow stromal cells. Exp Ther Med, 2013, 5(6): 1697-1700.
21. Saijo M, Kitazawa R, Nakajima M, et al. Heparanase mRNA expression during fracture repair in mice. Histochem Cell Biol, 2003, 120(6): 493-503.
22. Chuang CY, Lord MS, Melrose J, et al. Heparan sulfate dependent signaling of fibroblast growth factor (FGF) 18 by chondrocyte-derived perlecan. Biochemistry, 2010, 49(26): 5524-5532.
23. Manton KJ, Leong DF, Cool SM, et al. Disruption of heparan and chondroitin sulfate signaling enhances mesenchymal stem cell-derived osteogenic differentiation via bone morphogenetic protein signaling pathways. Stem Cells, 2007, 25(11): 2845-2854.
24. Genander M, Cook PJ, Ramsköld D, et al. BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages. Cell Stem Cell, 2014, 15(5): 619-633.
25. Jackson RA, McDonald MM, Nurcombe V, et al. The use of heparan sulfate to augment fracture repair in a rat fracture model. J Orthop Res, 2006, 24(4): 636-644.
26. Lafont J, Blanquaert F, Colombier ML, et al. Kinetic study of early regenerative effects of RGTA11, a heparan sulfate mimetic, in rat craniotomy defects. Calcif Tissue Int, 2004, 75(6): 517-525.
27. Gdalevitch M, Kasaai B, Alam N, et al. The effect of heparan sulfate application on bone formation during distraction osteogenesis. PLoS One, 2013, 8(2): e56790.
28. Woodruff MA, Rath SN, Susanto E, et al. Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model. J Mol Hist, 2007, 38(5): 425-433.
29. Rai B, Chatterjea A, Lim ZX, et al. Repair of segmental ulna defects using a β-TCP implant in combination with a heparan sulfate glycosaminoglycan variant. Acta Biomater, 2015, 28: 193-204.
30. Noble BS. The osteocyte lineage. Arch Biochem Biophys, 2008, 473(2): 106-111.
31. Wang B, Lai X, Price C, et al. Perlecan-containing pericellular matrix regulates solute transport and mechanosensing within the osteocyte lacunar-canalicular system. J Bone Miner Res, 2014, 29(4): 878-891.
32. Whitelock JM, Melrose J, Iozzo RV. Diverse cell signaling events modulated by perlecan. Biochemistry, 2008, 47(43): 11174-11183.
33. Lowe DA, Lepori-Bui N, Fomin PV, et al. Deficiency in perlecan/HSPG2 during bone development enhances osteogenesis and decreases quality of adult bone in mice. Calcif Tissue Int, 2014, 95(1): 29-38.
34. Ratzka A, Kalus I, Moser M, et al. Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. Dev Dyn, 2008, 237(2): 339-353.
35. Jackson RA, Nurcombe V, Cool SM. Coordinated fibroblast growth factor and heparan sulfate regulation of osteogenesis. Gene, 2006, 379: 79-91.
36. Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell, 2000, 103(2): 211-225.
37. Ellman MB, Yan D, Ahmadinia K, et al. Fibroblast growth factor control of cartilage homeostasis. J Cell Biochem, 2013, 114(4): 735-742.
38. Wu ZL, Zhang L, Yabe T, et al. The Involvement of Heparan Sulfate (HS) in FGF1/HS/FGFR1 Signaling Complex. J Biol Chem, 2003, 278(19): 17121-17129.
39. Debiais F, Lemonnier J, Hay E, et al. Fibroblast growth factor-2 increases N-cadherin expression through protein kinase C and Src-kinase pathways in human calvaria osteoblasts. J Cell Biochem, 2001, 81(1): 68-81.
40. Marie PJ. Fibroblast growth factor signaling controlling osteoblast differentiation. Gene, 2003, 316: 23-32.
41. Kim HJ, Kim JH, Bae SC, et al. The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J Biol Chem, 2003, 278(1): 319-326.
42. Mochly-Rosen D, Das K, Grimes KV. Protein kinase C, an elusive therapeutic target? Nat Rev Drug Discov, 2012, 11(12): 937-957.
43. 宋淑军, 张建中, 贾桂玥. 硫酸乙酰肝素通过 PKC 促进大鼠成骨细胞的增殖. 中国骨质疏松杂志, 2010, 16(5): 322-324.
44. Wolski H, Drews K, Bogacz A, et al. The RANKL/RANK/OPG signal trail: significance of genetic polymorphisms in the etiology of postmenopausal osteoporosis. Ginekol Pol, 2016, 87(5): 347-352.
45. Li M, Yang S, Xu D. Heparan sulfate regulates the structure and function of osteoprotegerin in osteoclastogenesis. J Biol Chem, 2016, 291(46): 24160-24171.
46. Bastami F, Paknejad Z, Jafari M, et al. Fabrication of a three-dimensional β-tricalcium-phosphate/gelatin containing chitosan-based nanoparticles for sustained release of bone morphogenetic protein-2: Implication for bone tissue engineering. Mater Sci Eng C Mater Biol Appl, 2017, 72: 481-491.
47. Bramono DS, Murali S, Rai B, et al. Bone marrow-derived heparan sulfate potentiates the osteogenic activity of bone morphogenetic protein-2 (BMP-2). Bone, 2012, 50(4): 954-964.
48. Murali S, Rai B, Dombrowski C, et al. Affinity-selected heparan sulfate for bone repair. Biomaterials, 2013, 34(22): 5594-5605.
49. Jiao X, Billings PC, O’Connell MP, et al. Heparan sulfate proteoglycans (HSPGs) modulate BMP2 osteogenic bioactivity in C2C12 cells. J Biol Chem, 2007, 282(2): 1080-1086.
50. Baht GS, Silkstone D, Nadesan P, et al. Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation. J Orthop Res, 2014, 32(4): 581-586.
51. Levi B, James AW, Nelson ER, et al. Role of Indian hedgehog signaling in palatal osteogenesis. Plast Reconstr Surg, 2011, 127(3): 1182-1190.

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