α2M对膝关节创伤后骨关节炎治疗作用的研究进展
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摘要
创伤后骨关节炎(PTOA)是由创伤引起的以关节软骨慢性退变为主要病理变化,以关节胀痛、活动功能障碍为主要临床表现的一种疾病。研究发现不论是半月板、滑膜损伤,交叉韧带撕裂还是随之而来的PTOA都有极其相似的病理过程,即创伤关节腔局部出现大量炎症因子、基质降解酶类物质,促使大量关节软骨细胞凋亡,导致关节软骨进一步退变。α2巨球蛋白(α2M)作为一种古老的高分子糖蛋白,其拥有多种活性形式和复杂的功能作用,在体内广泛参与物质的调节和转运,其广谱的蛋白酶抑制作用对PTOA及相关疾病患者有重要的保护作用。本文对于α2M这种保护作用进行综述,旨在为PTOA及相关疾病的预防和治疗提供依据。
Post-traumatic osteoarthritis(PTOA) is caused by trauma,which is pathologically characterized by chronic degeneration of articular cartilage with joint pain and activity dysfunction. Studies have found that meniscus injury, cruciate ligament tear, and accompanied PTOA have a similar pathological process. A large number of in?ammatory factors and matrix-degrading enzymes appear in the local wound of the knee joint, which causes apoptosis of a large number of articular cartilage cells and further degeneration of articular cartilage. Alpha-2-macroglobulin(α2M), as an ancient high-molecular glycoprotein, possesses a variety of active forms and complex functions and is widely involved in the regulation and transport of substances in the body. One of the roles of α2M is to act as a broad-spectrum protease inhibitor, which has a great protective effect against PTOA and related diseases. This article mainly reviews the research and application of α2M in PTOA and related diseases to improve their prevention and treatment.
Post-traumatic osteoarthritis(PTOA) is caused by trauma,which is pathologically characterized by chronic degeneration of articular cartilage with joint pain and activity dysfunction. Studies have found that meniscus injury, cruciate ligament tear, and accompanied PTOA have a similar pathological process. A large number of in?ammatory factors and matrix-degrading enzymes appear in the local wound of the knee joint, which causes apoptosis of a large number of articular cartilage cells and further degeneration of articular cartilage. Alpha-2-macroglobulin(α2M), as an ancient high-molecular glycoprotein, possesses a variety of active forms and complex functions and is widely involved in the regulation and transport of substances in the body. One of the roles of α2M is to act as a broad-spectrum protease inhibitor, which has a great protective effect against PTOA and related diseases. This article mainly reviews the research and application of α2M in PTOA and related diseases to improve their prevention and treatment.
引文
1 Alexander PG,Song Y,Taboas JM,et al.Development of a springloaded impact device to deliver injurious mechanical impacts to the articular cartilage surface[J].Cartilage,2013,4(1):52-62.
2 Lurie Y,Webb M,Cytter-Kuint R,et al.Non-invasive diagnosis of liver fibrosis and cirrhosis[J].World J Gastroenterol,2015,21(41):11567-11583.
3 Qian J,Ren C,Xia J,et al.Discovery,structural characterization and functional analysis of alpha-2-macroglobulin,a novel immune-related molecule from Holothuria atra[J].Gene,2016,585(2):205-215.
4 Cuéllar JM,Cuéllar VG,Scuderi GJ.α2-Macroglobulin:autologous protease inhibition technology[J].Phys Med Rehabil Clin N Am,2016:27(4):909-918.
5 Scuderi GJ,Montesano PX,Cuellar J.Improving Response To Treatment For Patients With Ddd With The Use Of The Fibronectinaggrecan Complex:1866 Board#18 June 2,2:00 PM-3:30 PM[J].Med Sci Sports Exerc,2016,48(5 Suppl 1):511-512.
6 Wang S,Wei X,Zhou J,et al.Identification ofα2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis[J].Arthritis Rheumatol,2014,66(7):1843-1853.
7 Andus T,Gross V,Tran-Thi TA,et al.The biosynthesis of acute-phase proteins in primary cultures of rat hepatocytes[J].Eur J Biochem,1983,133(3):561-571.
8 Woolley DE,Roberts DR,Evanson JM.Small molecular weight beta 1 serum protein which specifically inhibits human collagenase[J].Nature,1976,261(5558):325-327.
9 Bond JE,Cianciolo GJ,Pizzo SV.Incorporation of low molecular weight molecules into alpha(2)-macroglobulin by nucleophilic exchange[J].Biochem Biophys Res Commun,2007,357(2):433-438.
10 Craig-Barnes HA,Doumouras BS,Palaniyar N.Surfactant protein Dinteracts with alpha 2-macroglobulin and increases its innate immune potential[J].J Biol Chem,2010,285(18):13461-13470.
11 Ludvigsen M,Jacobsen C,Maunsbach AB,et al.Identification and characterization of novel ERC-55 interacting proteins:evidence for the existence of several ERC-55 splicing variants;including the cytosolic ERC-55-C[J].Proteomics,2009,9(23):5267-5287..
12 Woolley DE,Roberts DR,Evanson JM.Small molecular weigh beta 1 serum protein which specifically inhibits human collagenase[J].Nature(London),1976,261(5558):325-327.
13 Sottrup-Jensen L.Alpha-macroglobulin:structure,shape,and mechanism of proteinase complex formation[J].J Biol Chem,1989,264(20):11539-11542.
14 Rehman AA,Ahsan H,Khan FH.α-2-Macroglobulin:a physiological guardian[J].J Cell Physiol,2013,228(8):1665-1675.
15 Peslova G,Petrak J,Kuzelova K,et al.Hepcidin,the hormone of iron metabolism,is bound specifically to alpha-2-macroglobulin in blood[J].Blood,2009,113(24):6225-6236.
16 Solchaga LA,Hee CK,Roach S,et al.Safety of recombinant human platelet-derived growth factor-BB in Augment Bone Graft[J].J Tissue Eng,2012,3(1):2041731412442668.
17 Athippozhy A,Huang L,Wooton-Kee CR,et al.Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes[J].BMC Genomics,2011,12:95.
18 Hayes LN,Severance EG,Leek JT,et al.Inflammatory molecular signature associated with infectious agents in psychosis[J].Schizophr Bull,2014,40(5):963-972.
19 Birkenmeier G,K?mpfer I,Kratzsch J,et al.Human leptin forms complexes with alpha 2-macroglobulin which are recognized by the alpha 2-macroglobulin receptor/low density lipoprotein receptorrelated protein[J].Eur J Endocrinol,1998,139(2):224-230.
20 Luan Y,Kong L,Howell DR,et al.Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin[J].Osteoarthritis Cartilage,2008,16(11):1413-1420.
21 Tortorella MD,Arner EC,Hills R,et al.Alpha2-macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes[J].J Biol Chem,2004,279(17):17554-17561.
22 林子洪,何爱珊,傅明,等.前交叉韧带切除后半月板变化及α2-巨球蛋白干预效果的初步研究[J/CD].中华关节外科杂志(电子版),20l0,4(l):93-99.
23 Wan R,Hu J,Zhou Q,et al.Application of co-expressed genes to articular cartilage:new hope for the treatment of osteoarthritis(review)[J].Mol Med Rep,2012,6(1):16-18.
24 Ziskoven C,J?ger M,Zilkens C,et a1.Oxidative stress in secondary osteoarthritis:from cartilage destruction to clinical presentagion?[J].Orthop Rev(Pavia),2010,2(2):e23.
25 Zhang Y,Wei X,Browning S,et al.Targeted designed variants of alpha-2-macroglobulin(A2M)attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection[J].Arthritis Res Ther,2017,19(1):175-186.
26 Wei L,Fleming BC,Sun X,et al.Comparison of differential biomarkers of osteoarthritis with and without posttraumatic injury in the Hartley guinea pig model[J].J Orthop Res,2010,28(7):900-906.
27 Wei F,Moore DC,Wei L,et al.Attenuation of osteoarthritis via blockade of the SDF-1/CXCR4 signaling pathway[J].Arthritis Res Ther,2012,14(4):R177.
28 Du G,Zhan H,Ding D,et al.Abnormal mechanical loading induces cartilage degeneration by accelerating meniscus hypertrophy and mineralization after ACL injuries in vivo[J].Am J Sports Med,2016,44(3):652-663.
29 Haslauer CM,Elsaid KA,Fleming BC,et al.Loss of extracellular matrix from articular cartilage is mediated by the synovium and ligament after anterior cruciate ligament injury[J].Osteoarthritis Cartilage,2013,21(12):1950-1957.
30 Demirag B,Sarisozen B,Durak K,et al.The effect of alpha-2macroglobulin on the healing of ruptured anterior cruciate ligament in rabbits[J].Connect Tissue Res,2004,45(1):23-27.
2 Lurie Y,Webb M,Cytter-Kuint R,et al.Non-invasive diagnosis of liver fibrosis and cirrhosis[J].World J Gastroenterol,2015,21(41):11567-11583.
3 Qian J,Ren C,Xia J,et al.Discovery,structural characterization and functional analysis of alpha-2-macroglobulin,a novel immune-related molecule from Holothuria atra[J].Gene,2016,585(2):205-215.
4 Cuéllar JM,Cuéllar VG,Scuderi GJ.α2-Macroglobulin:autologous protease inhibition technology[J].Phys Med Rehabil Clin N Am,2016:27(4):909-918.
5 Scuderi GJ,Montesano PX,Cuellar J.Improving Response To Treatment For Patients With Ddd With The Use Of The Fibronectinaggrecan Complex:1866 Board#18 June 2,2:00 PM-3:30 PM[J].Med Sci Sports Exerc,2016,48(5 Suppl 1):511-512.
6 Wang S,Wei X,Zhou J,et al.Identification ofα2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis[J].Arthritis Rheumatol,2014,66(7):1843-1853.
7 Andus T,Gross V,Tran-Thi TA,et al.The biosynthesis of acute-phase proteins in primary cultures of rat hepatocytes[J].Eur J Biochem,1983,133(3):561-571.
8 Woolley DE,Roberts DR,Evanson JM.Small molecular weight beta 1 serum protein which specifically inhibits human collagenase[J].Nature,1976,261(5558):325-327.
9 Bond JE,Cianciolo GJ,Pizzo SV.Incorporation of low molecular weight molecules into alpha(2)-macroglobulin by nucleophilic exchange[J].Biochem Biophys Res Commun,2007,357(2):433-438.
10 Craig-Barnes HA,Doumouras BS,Palaniyar N.Surfactant protein Dinteracts with alpha 2-macroglobulin and increases its innate immune potential[J].J Biol Chem,2010,285(18):13461-13470.
11 Ludvigsen M,Jacobsen C,Maunsbach AB,et al.Identification and characterization of novel ERC-55 interacting proteins:evidence for the existence of several ERC-55 splicing variants;including the cytosolic ERC-55-C[J].Proteomics,2009,9(23):5267-5287..
12 Woolley DE,Roberts DR,Evanson JM.Small molecular weigh beta 1 serum protein which specifically inhibits human collagenase[J].Nature(London),1976,261(5558):325-327.
13 Sottrup-Jensen L.Alpha-macroglobulin:structure,shape,and mechanism of proteinase complex formation[J].J Biol Chem,1989,264(20):11539-11542.
14 Rehman AA,Ahsan H,Khan FH.α-2-Macroglobulin:a physiological guardian[J].J Cell Physiol,2013,228(8):1665-1675.
15 Peslova G,Petrak J,Kuzelova K,et al.Hepcidin,the hormone of iron metabolism,is bound specifically to alpha-2-macroglobulin in blood[J].Blood,2009,113(24):6225-6236.
16 Solchaga LA,Hee CK,Roach S,et al.Safety of recombinant human platelet-derived growth factor-BB in Augment Bone Graft[J].J Tissue Eng,2012,3(1):2041731412442668.
17 Athippozhy A,Huang L,Wooton-Kee CR,et al.Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes[J].BMC Genomics,2011,12:95.
18 Hayes LN,Severance EG,Leek JT,et al.Inflammatory molecular signature associated with infectious agents in psychosis[J].Schizophr Bull,2014,40(5):963-972.
19 Birkenmeier G,K?mpfer I,Kratzsch J,et al.Human leptin forms complexes with alpha 2-macroglobulin which are recognized by the alpha 2-macroglobulin receptor/low density lipoprotein receptorrelated protein[J].Eur J Endocrinol,1998,139(2):224-230.
20 Luan Y,Kong L,Howell DR,et al.Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin[J].Osteoarthritis Cartilage,2008,16(11):1413-1420.
21 Tortorella MD,Arner EC,Hills R,et al.Alpha2-macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes[J].J Biol Chem,2004,279(17):17554-17561.
22 林子洪,何爱珊,傅明,等.前交叉韧带切除后半月板变化及α2-巨球蛋白干预效果的初步研究[J/CD].中华关节外科杂志(电子版),20l0,4(l):93-99.
23 Wan R,Hu J,Zhou Q,et al.Application of co-expressed genes to articular cartilage:new hope for the treatment of osteoarthritis(review)[J].Mol Med Rep,2012,6(1):16-18.
24 Ziskoven C,J?ger M,Zilkens C,et a1.Oxidative stress in secondary osteoarthritis:from cartilage destruction to clinical presentagion?[J].Orthop Rev(Pavia),2010,2(2):e23.
25 Zhang Y,Wei X,Browning S,et al.Targeted designed variants of alpha-2-macroglobulin(A2M)attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection[J].Arthritis Res Ther,2017,19(1):175-186.
26 Wei L,Fleming BC,Sun X,et al.Comparison of differential biomarkers of osteoarthritis with and without posttraumatic injury in the Hartley guinea pig model[J].J Orthop Res,2010,28(7):900-906.
27 Wei F,Moore DC,Wei L,et al.Attenuation of osteoarthritis via blockade of the SDF-1/CXCR4 signaling pathway[J].Arthritis Res Ther,2012,14(4):R177.
28 Du G,Zhan H,Ding D,et al.Abnormal mechanical loading induces cartilage degeneration by accelerating meniscus hypertrophy and mineralization after ACL injuries in vivo[J].Am J Sports Med,2016,44(3):652-663.
29 Haslauer CM,Elsaid KA,Fleming BC,et al.Loss of extracellular matrix from articular cartilage is mediated by the synovium and ligament after anterior cruciate ligament injury[J].Osteoarthritis Cartilage,2013,21(12):1950-1957.
30 Demirag B,Sarisozen B,Durak K,et al.The effect of alpha-2macroglobulin on the healing of ruptured anterior cruciate ligament in rabbits[J].Connect Tissue Res,2004,45(1):23-27.