EFFECT OF Wnt/β-catenin SIGNAL PATHWAY ON APOPTOSIS IN STEROID-INDUCED AVASCULAR NECROSIS OF FEMORAL HEAD IN RATS_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHANGChen ¹ , LIMiao ² , MAJun ¹ , ZHANGEryang ¹ , BANWenrui ¹ , LüLeifeng ¹ , DANGXiaoqian ¹ ,  WANGKunzheng ¹

1. The First Department of Orthopaedics, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Shaanxi, 710004, P.R.China;
2. Department of Ultrasound, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an Shaanxi, 710004, P.R.China.;

Corresponding author：

WANGKunzheng, Email: wkzh1955@163.com

Keywords：

Steroid-induced avascular necrosis of femoral head; Apoptosis; Wnt/β-catenin signal pathway; Rat

DOI：

10.7507/1002-1892.20160135

Video：

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Objective To investigate the effect of Wnt/β-catenin signal pathway on the apoptosis in steroid-induced avascular necrosis of femoral head (SANFH) in rats. Methods Seventy-two male Sprague Dawley rats (weighing, 200-230 g) were randomly divided into the control group (group A, n=24), the model group (group B, n=24), and the intervening group (group C, n=24). The rats in groups B and C were injected with lipopolysaccharide and methylprednisolone (MPS) to establish the SANFH model. The rats in group C were injected intramuscularly with human recombinant secreted frizzled related protein 1 (SFRP1) [1 μg/(kg·d)] at the first time of MPS administration for 30 days. The rats in group A received saline injection at the same injection time of group B. The general condition of rats in groups B and C was observed during modeling and after modeling. At 2, 4, and 8 weeks after last injection of MPS, 8 rats were sacrificed to harvest the femoral head. Histological staining was performed to evaluate osteonecrosis. Apoptosis was detected via TUNEL staining. The expressions of Wnt/β-cate nin pathway signaling molecules (activated β-catenin and c-Myc) were detected by immunohistochemistry and Western blot. Results Six rats were added in groups B and C because of 6 deaths. The other rats survived to the end of experiment. Normal bone structure was observed in group A; osteonecrosis of bone structure disturbance and disruption of the trabecula were found with time in groups B and C. Group C had the highest empty lacuna rate and apoptosis rate, followed by groups B and A, showing significant difference between groups (P < 0.05). The expression levels of activated β-catenin and c-Myc were significantly lower in group C than groups A and B (P < 0.05), and in group B than group A (P < 0.05). Conclusion Wnt/β-catenin signal pathway is involved in the pathogenesis in early SANFH model and its possible mechanism is to affect the cell cycle and cell apoptosis by the regulation of c-Myc expression.

Citation： ZHANGChen, LIMiao, MAJun, ZHANGEryang, BANWenrui, LüLeifeng, DANGXiaoqian, WANGKunzheng. EFFECT OF Wnt/β-catenin SIGNAL PATHWAY ON APOPTOSIS IN STEROID-INDUCED AVASCULAR NECROSIS OF FEMORAL HEAD IN RATS. Chinese Journal of Reparative and Reconstructive Surgery, 2016, 30(6): 661-668. doi: 10.7507/1002-1892.20160135 Copy

1.	Mutijima E, De Maertelaer V, Deprez M, et al. The apoptosis of osteoblasts and osteocytes in femoral head osteonecrosis: its specificity and its distribution. Clin Rheumatol, 2014, 33(12): 1791-1795.
2.	Matsuo K. Glucocorticoid and Bone. Osteocytic osteolysis: potential modulation by glucocorticoids. Clin Cacium, 2014, 24(9):1337-1342.
3.	Wang J, Kalhor A, Lu S, et al. iNOS expression and osteocyte apoptosis in idiopathic, non-traumatic osteonecrosis. Acta Orthop, 2015, 86(1): 134-141.
4.	Weinstein RS, Jilka RL, Almeida M, et al. Intermittent parathyroid hormone administration counteracts the adverse effects of glucocorticoids on osteoblast and osteocyte viability, bone formation, and strength in mice. Endocrinology, 2010, 151(6): 2641-2649.
5.	Mollazadeh S, Fazly Bazzaz BS, Kerachian MA. Role of apoptosis in pathogenesis and treatment of bone-related diseases. J Orthop Surg Res, 2015, 10: 15.
6.	Mohammed MK, Shao C, Wang J, et al. Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis, 2016, 3(1): 11-40.
7.	Morris SL, Huang S. Crosstalk of the Wnt/β-catenin pathway with other pathways in cancer cells. Genes Dis, 2016, 3(1): 41-47.
8.	Wang Y, Li YP, Paulson C, et al. Wnt and the Wnt signaling pathway in bone development and disease. Front Biosci (Landmark Ed), 2014, 19: 379-407.
9.	Ying X, Chen X, Feng Y, et al. Myricetin enhances osteogenic differentiation through the activation of canonical Wnt/β-catenin signaling in human bone marrow stromal cells. Eur J Pharmacol, 2014, 738: 22-30.
10.	Duarte-Silva S, Neves-Carvalho A, Soares-Cunha C, et al. Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease. Cerebellum, 2014, 13(6): 713-727.
11.	Gao F, Zhang CQ, Chai YM, et al. Lentivirus-mediated Wnt10b overexpression enhances fracture healing in a rat atrophic non-union model. Biotechnol Lett, 2015, 37(3): 733-739.
12.	Duale N, Lipkin WI, Briese T, et al. Long-term storage of blood RNA collected in RNA stabilizing Tempus tubes in a large biobank—evaluation of RNA quality and stability. BMC Res Notes, 2014, 7: 633.
13.	Jackson A, Vayssière B, Garcia T, et al. Gene array analysis of Wnt-regulated genes in C3H10T1/2 cells. Bone, 2005, 36(4): 585-598.
14.	Burgers TA, Williams BO. Regulation of Wnt/β-catenin signaling within and from osteocytes. Bone, 2013, 54(2): 244-249.
15.	Elzi DJ, Song M, Hakala K, et al. Wnt antagonist SFRP1 functions as a secreted mediator of senescence. Mol Cell Biol, 2012, 32(21): 4388-4399.
16.	杨建平, 王黎明, 徐燕, 等. 单次低剂量脂多糖联合甲基强的松龙诱导股骨头坏死的实验研究. 中国修复重建外科杂志, 2008, 22(3): 271-275.
17.	Irisa T, Yamamoto T, Miyanishi K, et al. Osteonecrosis induced by a single administration of low-dose lipopolysaccharide in rabbits. Bone, 2001, 28(6): 641-649.
18.	Qin L, Zhang G, Sheng H, et al. Multiple bioimaging modalities in evaluation of an experimental osteonecrosis induced by a combination of lipopolysaccharide and methylprednisolone. Bone, 2006, 39(4): 863-871.
19.	Dees C, Schlottmann I, Funke R, et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis, 2014, 73(6): 1232-1239.
20.	Weinstein RS, Jilka RL, Parfitt AM, et al. Inhibition of osteoblast-ogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest, 1998, 102(2): 274-282.
21.	Jacobsen CM, Barber LA, Ayturk UM, et al. Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. J Bone Miner Res, 2014, 29(10): 2297-2306.
22.	Stoehr R, Wissmann C, Suzuki H, et al. Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab Invest, 2004, 84(4): 465-478.
23.	Lee JL, Chang CJ, Wu SY, et al. Secreted frizzled-related protein 2 (SFRP2) is highly expressed in canine mammary gland tumors but not in normal mammary glands. Breast Cancer Res Treat, 2004, 84(2): 139-149.
24.	Ren XY, Zhou GQ, Jiang W, et al. Low SFRP1 expression correlates with poor prognosis and promotes cell invasion by activating the Wnt/β-Catenin signaling pathway in NPC. Cancer Prev Res (Phila), 2015, 8(10): 968-977.
25.	Klein-Nulend J, van Oers RF, Bakker AD, et al. Nitric oxide signaling in mechanical adaptation of bone. Osteoporos Int, 2014, 25(5): 1427-1437.
26.	Pohl S, Scott R, Arfuso F, et al. Secreted frizzled-related protein 4 and its implications in cancer and apoptosis. Tumour Biol, 2014, 36(1): 143-152.
27.	Moore WJ, Kern JC, Bhat R, et al. Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides: part II. Bioorg Med Chem, 2010, 18(1): 190-201.
28.	Fu R, Liu H, Zhao S, et al. Osteoblast inhibition by chemokine cytokine ligand3 in myeloma-induced bone disease. Cancer Cell International, 2014, 14(1): 132-139.
29.	Xu L, Liu Y, Hou Y, et al. U0126 promotes osteogenesis of rat bone-marrow-derived mesenchymal stem cells by activating BMP/Smad signaling pathway. Cell Tissue Res, 2014, 359(2): 537-545.
30.	Gaur T, Rich L, Lengner CJ, et al. Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation. J Cell Physiol, 2006, 208(1): 87-96.
31.	Gaur T, Wixted JJ, Hussain S, et al. Secreted frizzled related protein 1 is a target to improve fracture healing. J Cell Physiol, 2009, 220(1): 174-181.

1. Mutijima E, De Maertelaer V, Deprez M, et al. The apoptosis of osteoblasts and osteocytes in femoral head osteonecrosis: its specificity and its distribution. Clin Rheumatol, 2014, 33(12): 1791-1795.
2. Matsuo K. Glucocorticoid and Bone. Osteocytic osteolysis: potential modulation by glucocorticoids. Clin Cacium, 2014, 24(9):1337-1342.
3. Wang J, Kalhor A, Lu S, et al. iNOS expression and osteocyte apoptosis in idiopathic, non-traumatic osteonecrosis. Acta Orthop, 2015, 86(1): 134-141.
4. Weinstein RS, Jilka RL, Almeida M, et al. Intermittent parathyroid hormone administration counteracts the adverse effects of glucocorticoids on osteoblast and osteocyte viability, bone formation, and strength in mice. Endocrinology, 2010, 151(6): 2641-2649.
5. Mollazadeh S, Fazly Bazzaz BS, Kerachian MA. Role of apoptosis in pathogenesis and treatment of bone-related diseases. J Orthop Surg Res, 2015, 10: 15.
6. Mohammed MK, Shao C, Wang J, et al. Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis, 2016, 3(1): 11-40.
7. Morris SL, Huang S. Crosstalk of the Wnt/β-catenin pathway with other pathways in cancer cells. Genes Dis, 2016, 3(1): 41-47.
8. Wang Y, Li YP, Paulson C, et al. Wnt and the Wnt signaling pathway in bone development and disease. Front Biosci (Landmark Ed), 2014, 19: 379-407.
9. Ying X, Chen X, Feng Y, et al. Myricetin enhances osteogenic differentiation through the activation of canonical Wnt/β-catenin signaling in human bone marrow stromal cells. Eur J Pharmacol, 2014, 738: 22-30.
10. Duarte-Silva S, Neves-Carvalho A, Soares-Cunha C, et al. Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease. Cerebellum, 2014, 13(6): 713-727.
11. Gao F, Zhang CQ, Chai YM, et al. Lentivirus-mediated Wnt10b overexpression enhances fracture healing in a rat atrophic non-union model. Biotechnol Lett, 2015, 37(3): 733-739.
12. Duale N, Lipkin WI, Briese T, et al. Long-term storage of blood RNA collected in RNA stabilizing Tempus tubes in a large biobank—evaluation of RNA quality and stability. BMC Res Notes, 2014, 7: 633.
13. Jackson A, Vayssière B, Garcia T, et al. Gene array analysis of Wnt-regulated genes in C3H10T1/2 cells. Bone, 2005, 36(4): 585-598.
14. Burgers TA, Williams BO. Regulation of Wnt/β-catenin signaling within and from osteocytes. Bone, 2013, 54(2): 244-249.
15. Elzi DJ, Song M, Hakala K, et al. Wnt antagonist SFRP1 functions as a secreted mediator of senescence. Mol Cell Biol, 2012, 32(21): 4388-4399.
16. 杨建平, 王黎明, 徐燕, 等. 单次低剂量脂多糖联合甲基强的松龙诱导股骨头坏死的实验研究. 中国修复重建外科杂志, 2008, 22(3): 271-275.
17. Irisa T, Yamamoto T, Miyanishi K, et al. Osteonecrosis induced by a single administration of low-dose lipopolysaccharide in rabbits. Bone, 2001, 28(6): 641-649.
18. Qin L, Zhang G, Sheng H, et al. Multiple bioimaging modalities in evaluation of an experimental osteonecrosis induced by a combination of lipopolysaccharide and methylprednisolone. Bone, 2006, 39(4): 863-871.
19. Dees C, Schlottmann I, Funke R, et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis, 2014, 73(6): 1232-1239.
20. Weinstein RS, Jilka RL, Parfitt AM, et al. Inhibition of osteoblast-ogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest, 1998, 102(2): 274-282.
21. Jacobsen CM, Barber LA, Ayturk UM, et al. Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. J Bone Miner Res, 2014, 29(10): 2297-2306.
22. Stoehr R, Wissmann C, Suzuki H, et al. Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab Invest, 2004, 84(4): 465-478.
23. Lee JL, Chang CJ, Wu SY, et al. Secreted frizzled-related protein 2 (SFRP2) is highly expressed in canine mammary gland tumors but not in normal mammary glands. Breast Cancer Res Treat, 2004, 84(2): 139-149.
24. Ren XY, Zhou GQ, Jiang W, et al. Low SFRP1 expression correlates with poor prognosis and promotes cell invasion by activating the Wnt/β-Catenin signaling pathway in NPC. Cancer Prev Res (Phila), 2015, 8(10): 968-977.
25. Klein-Nulend J, van Oers RF, Bakker AD, et al. Nitric oxide signaling in mechanical adaptation of bone. Osteoporos Int, 2014, 25(5): 1427-1437.
26. Pohl S, Scott R, Arfuso F, et al. Secreted frizzled-related protein 4 and its implications in cancer and apoptosis. Tumour Biol, 2014, 36(1): 143-152.
27. Moore WJ, Kern JC, Bhat R, et al. Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides: part II. Bioorg Med Chem, 2010, 18(1): 190-201.
28. Fu R, Liu H, Zhao S, et al. Osteoblast inhibition by chemokine cytokine ligand3 in myeloma-induced bone disease. Cancer Cell International, 2014, 14(1): 132-139.
29. Xu L, Liu Y, Hou Y, et al. U0126 promotes osteogenesis of rat bone-marrow-derived mesenchymal stem cells by activating BMP/Smad signaling pathway. Cell Tissue Res, 2014, 359(2): 537-545.
30. Gaur T, Rich L, Lengner CJ, et al. Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation. J Cell Physiol, 2006, 208(1): 87-96.
31. Gaur T, Wixted JJ, Hussain S, et al. Secreted frizzled related protein 1 is a target to improve fracture healing. J Cell Physiol, 2009, 220(1): 174-181.

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Chinese Journal of Reparative and Reconstructive Surgery

EFFECT OF Wnt/β-catenin SIGNAL PATHWAY ON APOPTOSIS IN STEROID-INDUCED AVASCULAR NECROSIS OF FEMORAL HEAD IN RATS

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