PROMOTION EFFECT OF FTY-720P ON TREATMENT OF BONE DEFECT WITH ALLOGRAFT BONE BY SUPPRESSING OSTEOCLAST FORMATION AND FUNCTION_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

HUANGYongjun ¹ ,  HUANGDong ¹ , ZHANGDawei ² , MOUYong ¹ , LIUXiaochun ¹

1. Department of Traumatic Orthopaedics, Guangdong No.2 Provincial People's Hospital, Guangzhou Guangdong, 510317, P. R. China;
2. Department of Spinal Surgery, the Fifth Affiliated Hospital of Sun Yat-sen University;

Corresponding author：

HUANGDong, Email: dong-177@163.com

Keywords：

FTY-720P; Allograft bone; Bone marrow-derived mononuclear phagocytes; Osteoclast; Mechanisms research

DOI：

10.7507/1002-1892.20160086

Video：

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Objective To explore whether FTY-720P could enhance the effect of allograft bone for bone defect repair by suppressing osteoclast formation and function. Method Animal experiment:Forty-eight New Zealand white rabbits were selected to establish the tibia defect model (1.5 cm in length) and were divided into 4 groups (n=12) . Defect was not repaired in group A, defect was repaired with allograft bone in group B, with autogenous fibula in group C, and with allograft bone and FTY-720P in group D. Lane-Sandhu scoring system and bone density examination were used to evaluate the effect at 2, 4, 8, and 12 weeks after operation. Cell experiment:Bone marrow-derived mononuclear phagocytes (BMMs) were harvested from 1-month-old Sprague Dawley rats and induced into osteoclasts with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL), then were identified with tartrate-resistant acid phosphatas (TRAP). According to different concentrations of FTY-720P before induction, experiment was divided into 0, 500, 600, 700, 800, 900, 1 000, and 1 500 ng/mL groups. The effect of FTY-720P was studied by counting the number of osteoclasts and the number of bone resorption lacunae made by osteoclasts. Results Animal experiment:Lane-Sandhu score showed no significant difference between groups at 2 weeks after operation (P>0.05) , but the score was significantly better in groups C and D than groups A and B, and in group B than group A (P<0.05) . The bone density of group C was significantly greater than that of groups A, B, and D at 2 weeks after operation (P<0.05) , but no significant difference was found among groups A, B, and D (P>0.05) ; the bone density of groups B, C, and D was significantly greater than that of group A at 4, 8, and 12 weeks (P<0.05) , but no significant difference was shown among groups B, C, and D (P>0.05) . Cell experiment:BMMs could be induced into osteoclasts by the addition of M-CSF and RANKL, which could be proved by counting the number of the nuclear and TRAP staining. The osteoclasts were significantly more in 0, 500, 600, 700, 800, 900 ng/mL groups than 1 000 and 1 500 ng/mL groups (P<0.05) , in 0, 500, 600, and 700 ng/mL groups than 800 and 900 ng/mL groups (P<0.05) , in 0, 500, 600 ng/mL groups than 700 ng/mL group (P<0.05) ; and there was no significant difference between the other groups (P>0.05) . The number of bone resorption lacunae in 0, 500, 600, and 700 ng/mL groups was significantly higher than that in 800, 900, 1 000, and 1 500 ng/mL groups (P<0.05) , and it was significantly higher in 0, 500 and 600 ng/mL groups than 700 ng/mL group (P<0.05) , but difference was not significant between the other groups (P>0.05) . Conclusions FTY-720P combined with allograft bone for bone defect repair can have the same effect to autogenous bone by means of inhibiting osteoclast formation and function, which reduces bone loss.

Citation： HUANGYongjun, HUANGDong, ZHANGDawei, MOUYong, LIUXiaochun. PROMOTION EFFECT OF FTY-720P ON TREATMENT OF BONE DEFECT WITH ALLOGRAFT BONE BY SUPPRESSING OSTEOCLAST FORMATION AND FUNCTION. Chinese Journal of Reparative and Reconstructive Surgery, 2016, 30(4): 426-431. doi: 10.7507/1002-1892.20160086 Copy

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2.	Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med, 2010, 362(5) :387-401.
3.	Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 2002, 296(5566) :346-349.
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7.	唐坚, 孙月华. β-磷酸三钙与异体骨植骨治疗跟骨关节内骨折的比较研究. 中国骨与关节损伤杂志, 2006, 21(6) :447-449.
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10.	Sawicka E, Dubois G, Jarai G, et al. The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity. J Immunol, 2005, 175(12) :7973-7980.
11.	Huang C, Das A, Barker D, et al. Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation. Cell Tissue Res, 2012, 347(3) :553-566.
12.	Chambers TJ, Revell PA, Fuller K, et al. Resorption of bone by isolated rabbit osteoclasts. J Cell Sci, 1984, 66:383-399.
13.	Udagawa N, Takahashi N, Akatsu T, et al. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology, 1989, 125(4) :1805-1813.
14.	Shin J, Jang H, Lin J, et al. PKCβ positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3β. Mol Cells, 2014, 37(10) :747-752.
15.	Zhai ZJ, Li HW, Liu GW, et al. Andrographolide suppresses RANKL induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo. Br J Pharmacol, 2014, 171(3) :663-675.
16.	Yu MX, Chen XY, Lv CY, et al. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway. Biochem Biophy Res Commun, 2014, 447(2) :364-370.
17.	Tian B, Jiang T, Shao ZY, et al. The prevention of titanium particle-induced osteolysis by OA-14 through the suppression of the p38 signaling pathway and inhibition of osteoclastogenesis. Biomaterials, 2014, 35(32) :8937-8950.
18.	Kim JH, Kim N. Regulation of NFATc1 in osteoclast differentiation. J Bone Metab, 2014, 21(4) :233-241.
19.	Kato K, Matsushita M. Proton concentrations can be a major contributor to the modification of osteoclast and osteoblast differentiation, working independently of extracellular bicarbonateions. J Bone Miner Metab, 2014, 32(1) :17-28.
20.	Ryu J, Kim HJ, Chang EJ, et al. Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J, 2006, 25(24) :5840-5851.

1. Wheeler DL, Enneking WF. Allograft bone decreases in strength in vivo over time. Clin Orthop Relat Res, 2005, (435) :36-42.
2. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med, 2010, 362(5) :387-401.
3. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 2002, 296(5566) :346-349.
4. de Girolamo L, Arrigoni E, Stanco D, et al. Role of autologous rabbitadiposederived stem cells in the early phases of the repairingprocess of critical bone defects. J Orthop Res, 2011, 29(1) :100-108.
5. Lane JM, Sandhu HS. Current approaches to experimental bone grafting. Orthop Clin North Am, 1982, 18(2) :213-225.
6. 王鑫, 史册, 郑嵘, 等. 白细胞介素-24 对破骨细胞功能及分化的影响. 实用口腔医学杂志, 2014, 30(4) :456-459.
7. 唐坚, 孙月华. β-磷酸三钙与异体骨植骨治疗跟骨关节内骨折的比较研究. 中国骨与关节损伤杂志, 2006, 21(6) :447-449.
8. 韦盛旺, 赵友明. 跟骨骨折手术治疗的植骨现状. 中国骨与关节损伤杂志, 2011, 26(8) :767-768.
9. Oo ML, Thangada S, Wu MT, et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem, 2007, 282(12) :9082-9089.
10. Sawicka E, Dubois G, Jarai G, et al. The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity. J Immunol, 2005, 175(12) :7973-7980.
11. Huang C, Das A, Barker D, et al. Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation. Cell Tissue Res, 2012, 347(3) :553-566.
12. Chambers TJ, Revell PA, Fuller K, et al. Resorption of bone by isolated rabbit osteoclasts. J Cell Sci, 1984, 66:383-399.
13. Udagawa N, Takahashi N, Akatsu T, et al. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology, 1989, 125(4) :1805-1813.
14. Shin J, Jang H, Lin J, et al. PKCβ positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3β. Mol Cells, 2014, 37(10) :747-752.
15. Zhai ZJ, Li HW, Liu GW, et al. Andrographolide suppresses RANKL induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo. Br J Pharmacol, 2014, 171(3) :663-675.
16. Yu MX, Chen XY, Lv CY, et al. Curcumol suppresses RANKL-induced osteoclast formation by attenuating the JNK signaling pathway. Biochem Biophy Res Commun, 2014, 447(2) :364-370.
17. Tian B, Jiang T, Shao ZY, et al. The prevention of titanium particle-induced osteolysis by OA-14 through the suppression of the p38 signaling pathway and inhibition of osteoclastogenesis. Biomaterials, 2014, 35(32) :8937-8950.
18. Kim JH, Kim N. Regulation of NFATc1 in osteoclast differentiation. J Bone Metab, 2014, 21(4) :233-241.
19. Kato K, Matsushita M. Proton concentrations can be a major contributor to the modification of osteoclast and osteoblast differentiation, working independently of extracellular bicarbonateions. J Bone Miner Metab, 2014, 32(1) :17-28.
20. Ryu J, Kim HJ, Chang EJ, et al. Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J, 2006, 25(24) :5840-5851.

Chinese Journal of Reparative and Reconstructive Surgery

PROMOTION EFFECT OF FTY-720P ON TREATMENT OF BONE DEFECT WITH ALLOGRAFT BONE BY SUPPRESSING OSTEOCLAST FORMATION AND FUNCTION

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