李彥林 1 , 王國梁 1 , 曹斌 2 , 高崗 1 , 馬珂 1 , 陳文棟 1 , 許鵬 1 , 楊光 1
  • 1 昆明醫(yī)學(xué)院第一附屬醫(yī)院運(yùn)動醫(yī)學(xué)科（昆明，650000）;;
  • 2 湖南省第二人民醫(yī)院骨科;

目的 探討趨化因子受體4（chemokine receptor 4，CXCR4）特異性拮抗劑AMD3100 體外阻斷基質(zhì)細(xì)胞衍生因子1 （stromal cell derived factor 1，SDF-1）/CXCR4 信號通路對人關(guān)節(jié)軟骨細(xì)胞分泌基質(zhì)金屬蛋白酶（matrix metalloproteinase，MMP）3、9、13 水平的影響，明確AMD3100 的作用機(jī)制。 方法 取12 例骨關(guān)節(jié)炎（osteoarthritis，
OA）患者144 塊軟骨組織（OA 軟骨組）和12 例創(chuàng)傷性截肢患者144 塊正常軟骨組織（正常軟骨組）（Mankin 評分均為
0 或1），根據(jù)添加培養(yǎng)液不同，每組再分為A、B、C 3 個亞組。A 亞組含1 000 nmol/L AMD3100 及100 ng/mL SDF-1 的
DMEM 液，B 亞組含1 000 nmol/L MAB310 及100 ng/mL SDF-1 的DMEM 液， C 亞組含100 ng/mL SDF-1 的DMEM
液。體外培養(yǎng)2、4 d 后，ELISA 法測定培養(yǎng)液內(nèi)MMP-3、9、13 含量，RT-PCR 檢測軟骨組織中MMP-3、9、13 mRNA 表
達(dá)。 結(jié)果 ELISA 法及RT-PCR 檢測示：同組相同時間點(diǎn)A 亞組MMP-3、9、13 含量及mRNA 表達(dá)均顯著低于B、C
亞組（P  lt; 0.05）。同一時間點(diǎn)相同亞組OA軟骨組MMP-3、9、13 含量及mRNA表達(dá)均顯著高于正常軟骨組（P  lt; 0.05）。 結(jié)論 SDF-1 通過SDF-1/CXCR4 信號通路可誘導(dǎo)人關(guān)節(jié)軟骨中MMP-3、9、13 的表達(dá)和釋放；AMD3100 可阻斷SDF-1/
CXCR4 信號通路，使軟骨細(xì)胞MMP-3、9、13 mRNA 表達(dá)水平及分泌量降低，但AMD3100 不能使退變的OA 軟骨分泌
MMP-3、9、13 恢復(fù)至正常軟骨水平。

引用本文： 李彥林,王國梁,曹斌,高崗,馬珂,陳文棟,許鵬,楊光. AMD3100 體外阻斷基質(zhì)細(xì)胞衍生因子1/ 趨化因子受體4信號通路對人關(guān)節(jié)軟骨細(xì)胞分泌基質(zhì)金屬蛋白酶 3、9、13 水平的影響. 中國修復(fù)重建外科雜志, 2012, 26(6): 652-656. doi: 復(fù)制

1. Elsaid KA, Machan JT, Waller K, et al. The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting tumor necrosis factor alpha on chondroprotection in an animal model. Arthritis Rheum, 2009, 60(10): 2997-3006.
2. Hendren L, Beeson P. A review of the differences between normal and osteoarthritis articular cartilage in human knee and ankle joints. The Foot, 2009, 19(3): 171-176.
3. Wei L, Sun X, Kanbe K, et al. Chondrocyte death induced by pathological concentration of chemokine Stromal cell-derived factor-1. J Rheumatol, 2006, 33(9): 1818-1826.
4. Lisgnoli G, Toneguzzi S, Piacentini A, et al. CXCL12 (SDF-1) and CXCL13 (BCA-1) chemokines significantly induce proliferation and collagen type I expression in osteoblasts from osteoarthritis patients. J Cell Physiol, 2006, 206(1): 78-85.
5. Ross JM, Sherwin AF, Poole CA. In vitro culture of enzymatieally isolated ehondron: a possible model for the initiation of osteoarthritis. J Anat, 2006, 209(6): 793-806.
6. Altman RD. The classification of osteoarthritis. J Rheumatol Suppl, 1995, 43: 42-43.
7. Flannery CR, Little CB, Caterson B, et al. Effects of culture conditions and exposure to catabolic stimulators (IL-1 and retinoic acid) on the expression of matrix metalloproteinases (MMPs) and disintegrin metalloproteinases (ADAMs) by articular cartilage chondrocytes. Matrix Biol, 1999, 18(3): 225-237.
8. Mitchell PG, Mogna HA, Reeves LM, et al. Cloning, expression and type Ⅱ collagenolytic activity of matrix metalloprpteinase-13 from human osteoarthritis cartilage. J Clin Invest, 1996, 97(3): 761-768.
9. 班吉鶴, 周利武, 毛廣平, 等. 應(yīng)用蛋白質(zhì)芯片檢測骨性關(guān)節(jié)炎患者基質(zhì)金屬蛋白酶-13的初步研究. 醫(yī)學(xué)研究生學(xué)報, 2008, 21(8): 836-838, 844.
10. Kanbe K, Takagishi K, Chen Q. Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4. Arthritis Rheum, 2002, 46(1): 130-137.
11. D’APuzzo M, Rolink A, Loetscher M, et al. The chemokine SDF-l, stromal cell-derivcd factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol, 1997, 27(7): 1788-1793.
12. Santiago B, Baleux F, Palao G, et al. CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans. Arthritis Res Ther, 2006, 8(2): R43.
13. Chiu YC, Yang RS, Hsieh KH, et al. Stromal cell-derived factor-1 induces matrix metalloprotease-13 expression in human chondrocytes. Mol Pharmacol, 2007, 72(3): 695-703.
14. Matthys P, Hatse S, Vermeire, et al. AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-gamma receptor deficient mice. J Immunology, 2001, 167(8): 4686-4692.
15. Blanco J, Barretina J, Henson G, et al. The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis. Antimicrob Agents Chemother, 2000, 44(1): 51-56.
16. Hatse S, Princen K, Bridger G, et al. Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett, 2002, 527(1-3): 255-262.
17. De Clercq E. The bicyclam AMD3100 story. Nat Rev Drug Discov, 2003, 2(7): 581-587.
18. 李曉林, 李彥林, 馬珂, 等. SDF-1/CXCR4信號通路在骨性關(guān)節(jié)炎病理進(jìn)程中的作用. 中國組織工程研究與臨床康復(fù), 2011, 15(15): 2805-2808.
19. Tamamura H, Tsutsumi H, Masuno H, et al. Development of low molecular weight CXCR4 antagonists by exploratory structural tuning of cyclic tetra and pentapeptide-scaffolds towards the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. Curr Med Chem, 2007, 14(1): 93-102.
20. De Klerck B, Geboes L, Hatse S, et al. Pro-inflammatory properties of stromal cell-derived factor-1 (CXCL12) in collagen-induced arthritis. Arthritis Res Ther, 2005, 7(6): R1208-1220.
  1. 1. Elsaid KA, Machan JT, Waller K, et al. The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting tumor necrosis factor alpha on chondroprotection in an animal model. Arthritis Rheum, 2009, 60(10): 2997-3006.
  2. 2. Hendren L, Beeson P. A review of the differences between normal and osteoarthritis articular cartilage in human knee and ankle joints. The Foot, 2009, 19(3): 171-176.
  3. 3. Wei L, Sun X, Kanbe K, et al. Chondrocyte death induced by pathological concentration of chemokine Stromal cell-derived factor-1. J Rheumatol, 2006, 33(9): 1818-1826.
  4. 4. Lisgnoli G, Toneguzzi S, Piacentini A, et al. CXCL12 (SDF-1) and CXCL13 (BCA-1) chemokines significantly induce proliferation and collagen type I expression in osteoblasts from osteoarthritis patients. J Cell Physiol, 2006, 206(1): 78-85.
  5. 5. Ross JM, Sherwin AF, Poole CA. In vitro culture of enzymatieally isolated ehondron: a possible model for the initiation of osteoarthritis. J Anat, 2006, 209(6): 793-806.
  6. 6. Altman RD. The classification of osteoarthritis. J Rheumatol Suppl, 1995, 43: 42-43.
  7. 7. Flannery CR, Little CB, Caterson B, et al. Effects of culture conditions and exposure to catabolic stimulators (IL-1 and retinoic acid) on the expression of matrix metalloproteinases (MMPs) and disintegrin metalloproteinases (ADAMs) by articular cartilage chondrocytes. Matrix Biol, 1999, 18(3): 225-237.
  8. 8. Mitchell PG, Mogna HA, Reeves LM, et al. Cloning, expression and type Ⅱ collagenolytic activity of matrix metalloprpteinase-13 from human osteoarthritis cartilage. J Clin Invest, 1996, 97(3): 761-768.
  9. 9. 班吉鶴, 周利武, 毛廣平, 等. 應(yīng)用蛋白質(zhì)芯片檢測骨性關(guān)節(jié)炎患者基質(zhì)金屬蛋白酶-13的初步研究. 醫(yī)學(xué)研究生學(xué)報, 2008, 21(8): 836-838, 844.
  10. 10. Kanbe K, Takagishi K, Chen Q. Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4. Arthritis Rheum, 2002, 46(1): 130-137.
  11. 11. D’APuzzo M, Rolink A, Loetscher M, et al. The chemokine SDF-l, stromal cell-derivcd factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol, 1997, 27(7): 1788-1793.
  12. 12. Santiago B, Baleux F, Palao G, et al. CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans. Arthritis Res Ther, 2006, 8(2): R43.
  13. 13. Chiu YC, Yang RS, Hsieh KH, et al. Stromal cell-derived factor-1 induces matrix metalloprotease-13 expression in human chondrocytes. Mol Pharmacol, 2007, 72(3): 695-703.
  14. 14. Matthys P, Hatse S, Vermeire, et al. AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflammation in IFN-gamma receptor deficient mice. J Immunology, 2001, 167(8): 4686-4692.
  15. 15. Blanco J, Barretina J, Henson G, et al. The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis. Antimicrob Agents Chemother, 2000, 44(1): 51-56.
  16. 16. Hatse S, Princen K, Bridger G, et al. Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett, 2002, 527(1-3): 255-262.
  17. 17. De Clercq E. The bicyclam AMD3100 story. Nat Rev Drug Discov, 2003, 2(7): 581-587.
  18. 18. 李曉林, 李彥林, 馬珂, 等. SDF-1/CXCR4信號通路在骨性關(guān)節(jié)炎病理進(jìn)程中的作用. 中國組織工程研究與臨床康復(fù), 2011, 15(15): 2805-2808.
  19. 19. Tamamura H, Tsutsumi H, Masuno H, et al. Development of low molecular weight CXCR4 antagonists by exploratory structural tuning of cyclic tetra and pentapeptide-scaffolds towards the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. Curr Med Chem, 2007, 14(1): 93-102.
  20. 20. De Klerck B, Geboes L, Hatse S, et al. Pro-inflammatory properties of stromal cell-derived factor-1 (CXCL12) in collagen-induced arthritis. Arthritis Res Ther, 2005, 7(6): R1208-1220.