KLF5和MMP-9表达与膝关节软骨神经血管侵入关系的临床研究
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摘要
目的:观察Kruppel样因子5(krüppel-like factor 5,KLF5)和基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)表达活性与骨关节炎患者膝关节软骨血管及神经纤维侵入情况之间的关系。
方法与结果:于河北医科大学第三医院关节外科随机选取20例行全膝关节置换术的患者,男性3例、女性17例,平均年龄67.2岁( 55 - 74岁),均为患者及家属知情同意。在术中截骨中获取胫骨平台(包括软骨及软骨下骨),区分磨损与相对无磨损区域;选取31个关节标本,将每个标本切割成2-3块(边长大约为0.5cm),并分成磨损组(SC,n=29)和无磨损组(NC,n=17)。将所有标本置于10%的福尔马林溶液中浸泡保存,以便进行各种染色。
番红O及HE染色可见,在磨损组的关节软骨潮线附近有血管化发生,扫描电镜也证实血管结构的存在;关节软骨的神经侵袭仅发生于血管化的标本;与无磨损的关节软骨区比较,磨损区的血管化和神经支配数量明显增加(P<0.05)。
免疫组化染色可见,在磨损组的关节软骨中, KLF-5、MMP-9的表达活性明显高于无磨损组(P<0.05),而且,与血管侵袭程度具有正相关关系。
结论:骨关节炎关节软骨的神经侵袭是发生于血管化后的继发病变。病变区域增加的KLF-5和MMP-9表达可能是骨关节炎软骨退变和神经血管化的重要机制之一。
Objective: To investigate the relationship between the expression of factor of krüppel-like factor (KLF)-5,matrix metalloproteinase-9(MMP-9)and neurovascular invasion in osteophytes in osteoarthritis (OA).
Methods and results: 31 articular cartilage samples were collected from 20 patients who had undergone total knee arthroplasty (TKA), and each sample was divided into two groups, no change (NC, n=17) and severe change (SC, n=29) according to Mankin score and safranin O staining. Neurovascular markers protein gene product (PGP) 9.5 and CD34, and the expression of KLF-5,MMP-9 were detected by immunohistochemistry.
Vascular channels were observed in both NC and SC sections. In SC sections, 16/29 (55.2%) sections displayed vessels entering the calcified cartilage, which was more than that in NC group (2/17, 11.7%, P<0.05). The frequency of neurovascular invasion was significantly different between SC and NC (P<0.05). Innervation always accompanied vascular invasion at the osteochondral junction. The severity of neurovascular invasion was positively correlated with the expression of KLF5 and MMP-9 in chondrocytes at the same site that was significantly different between SC and NC samples.
Conclusions: KLF5-induced MMP-9 expression may be involved in cartilage matrix degradation and vascularization.
方法与结果:于河北医科大学第三医院关节外科随机选取20例行全膝关节置换术的患者,男性3例、女性17例,平均年龄67.2岁( 55 - 74岁),均为患者及家属知情同意。在术中截骨中获取胫骨平台(包括软骨及软骨下骨),区分磨损与相对无磨损区域;选取31个关节标本,将每个标本切割成2-3块(边长大约为0.5cm),并分成磨损组(SC,n=29)和无磨损组(NC,n=17)。将所有标本置于10%的福尔马林溶液中浸泡保存,以便进行各种染色。
番红O及HE染色可见,在磨损组的关节软骨潮线附近有血管化发生,扫描电镜也证实血管结构的存在;关节软骨的神经侵袭仅发生于血管化的标本;与无磨损的关节软骨区比较,磨损区的血管化和神经支配数量明显增加(P<0.05)。
免疫组化染色可见,在磨损组的关节软骨中, KLF-5、MMP-9的表达活性明显高于无磨损组(P<0.05),而且,与血管侵袭程度具有正相关关系。
结论:骨关节炎关节软骨的神经侵袭是发生于血管化后的继发病变。病变区域增加的KLF-5和MMP-9表达可能是骨关节炎软骨退变和神经血管化的重要机制之一。
Objective: To investigate the relationship between the expression of factor of krüppel-like factor (KLF)-5,matrix metalloproteinase-9(MMP-9)and neurovascular invasion in osteophytes in osteoarthritis (OA).
Methods and results: 31 articular cartilage samples were collected from 20 patients who had undergone total knee arthroplasty (TKA), and each sample was divided into two groups, no change (NC, n=17) and severe change (SC, n=29) according to Mankin score and safranin O staining. Neurovascular markers protein gene product (PGP) 9.5 and CD34, and the expression of KLF-5,MMP-9 were detected by immunohistochemistry.
Vascular channels were observed in both NC and SC sections. In SC sections, 16/29 (55.2%) sections displayed vessels entering the calcified cartilage, which was more than that in NC group (2/17, 11.7%, P<0.05). The frequency of neurovascular invasion was significantly different between SC and NC (P<0.05). Innervation always accompanied vascular invasion at the osteochondral junction. The severity of neurovascular invasion was positively correlated with the expression of KLF5 and MMP-9 in chondrocytes at the same site that was significantly different between SC and NC samples.
Conclusions: KLF5-induced MMP-9 expression may be involved in cartilage matrix degradation and vascularization.
引文
1 Suri S, Gill SE, Camin SM de, et al. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann Rheum Dis, 2007, 66:1423-1428
2 Madsen JE, Hukkanen M, Aspenberg P, et al. Time-dependent sensory nerve ingrowth into a bone conduction chamber. Acta Orthop Scand 2000, 71:74-79
3 Embree MC, Kilts TM, Ono M, et al. Biglycan and fibromodulin have essential roles in regulating chondrogenesis and extracellular matrix turnover in temporomandibular joint osteoarthritis. Am J Pathol 2010, 176: 812-826
4 Mapp PI, Walsh DA, Bowyer J, Maciewicz RA. Effects of a metalloproteinase inhibitor on osteochondral angiogenesis, chondropathy and pain behavior in a rat model of osteoarthritis. Osteoarthritis Cartilage 2010, 18:593-600
5 Li A, Zhang Y, Lao L, at al. Serotonin receptor 2A/C is involved in electroacupuncture inhibition of pain in an osteoarthritis rat model. eCAM 2010, doi:10.1093/ecam/neq016
6 Shinoda Y, Ogata N, Higashikawa A, et al. Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9. J Biol Chem, 2008, 283(36): 24682-24689
1 Chen KH, Guo X, Ma D, et al. Dysregulation of HSG triggers vascular proliferative disorders [J]. Nature Cell Biol, 2004; 6: 872-83
2 Wang C, Han M, Zhao XM, Wen JK. Krüppel-like factor 4 is required for the expression of vascular smooth muscle cell differentiation marker genes induced by all-trans retinoic acid [J]. J Biochem, 2008, 144, 313-21
3 Shields JM, Christy RJ, Yang VW. Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem, 1996, 271(33): 20009-20017
4 Dang DT, Mahatan CS, Dang LH, et al. Expression of the gut-enriched kruppel-like factor (kruppel-like factor 4) gene in the human colon cancer cell line RKO is dependent on C DX2. Oncogene, 2001, 20(35): 4884-4890
5温进坤,韩梅.医学分子生物学理论与研究技术[M],北京:科学出版社,2001:296-7
1 Felson DT, Chaisson CE, Hill CL et al. The association of bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med 2001;134:541-9
2 YASUSHI AKAMATSU, NAOTO MITSUGI, NAOYA TAKI, RYOHEI TAKEUCHI, and TOMOYUKI SAITO. Relationship Between Low Bone Mineral Density and Varus Deformity in Postmenopausal Women with Knee Osteoarthritis .J Rheumatol Mar 2009; 36: 592-597
3 Jarvholm B, From C, Lewold S, Malchau H, and Ving?rd E. Incidence of surgically treated osteoarthritis in the hip and knee in male construction workers. Occup. Environ. Med., Apr 2008; 65: 275-278
4 Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 2001;286:188-95
5 Spector TD, MacGregor AJ. Risk factors for osteoarthritis: genetics. Osteoarthr Cartilage 2004;12(Suppl A):S39-44
6 Brandi ML, Collin-Osdoby P. Vascular biology and the skeleton. J Bone Miner Res 2006;21:183-92
7 Compston JE. Bone marrow and bone: a functional unit. J Endocrinol 2002;173:387-94
8 Satoru Otsuru, Katsuto Tamai, Takehiko Yamazaki, Hideki Yoshikawa, and Yasufumi Kaneda. Circulating Bone Marrow-Derived Osteoblast Progenitor Cells Are Recruited to the Bone-Forming Site by the CXCR4/Stromal Cell-Derived Factor-1 Pathway. Stem Cells, Jan 2008; 26: 223-234
9 Johnson EO, Soultanis K, Soucacos PN. Vascular anatomy and microcirculation of skeletal zones vulnerable to osteonecrosis: vascularization of the femoral head. Orthop Clin North Am 2004;35:285-91
10 Cowin SC. The plumbing of bone. In: Cerrolaza M, Mart?′nez G, Doblare′M, Calvo B, eds. Computational bioengineering: current trends and applications. World Scientific Publishing (UK): Imperial College Press, 2004;41-59
11 Imhof H, Breitenseher M, Kainberger F, Trattnig S. Degenerative joint disease: cartilage or vascular disease? Skeletal Radiol 1997;26:398-403
12 Reeve J, Arlot M, Wootton R et al. Skeletal blood flow, iliac histomorphometry, and strontium kinetics in osteoporosis: a relationship between blood flow and corrected apposition rate. J Clin Endocrinol Metab 1988;66:1124-31
13 Boraiah S., Dyke J. P., Hettrich C., Parker R. J., Miller A., Helfet D., and Lorich D.. Assessment of vascularity of the femoral head using gadolinium (Gd-DTPA)-enhanced magnetic resonance imaging: A CADAVER STUDY. J Bone Joint Surg Br; Jan 2009; 91-B: 131-137
14 Seeman E. Osteocytes-martyrs for integrity of bone strength. Osteoporos Int 2006;17:1443-8
15 You LD, Weinbaum S, Cowin SC, Schaffler MB. Ultrastructure of the osteocyte process and its pericellular matrix. Anat Rec a Discov Mol Cell Evol Biol 2004;278:505-13
16 Noble B. Microdamage and apoptosis. Eur J Morphol 2005;42:91–8. 24 Winkler DG, Sutherland MK, Geoghegan JC et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003;22:6267-76
17 Winkler DG, Sutherland MK, Geoghegan JC et al. Osteocyte controlof bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003;22:6267-76
18 Feng JQ, Ward LM, Liu S et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006;38:1310-5
19 Carrino JA, Blum J, Parellada JA, Schweitzer ME, Morrison WB. MRI of bone marrow edema-like signal in the pathogenesis of subchondral cysts. Osteoarthritis Cartilage 2006;14:1081-5
20 From AM., Hyder JA., Kearns AE., Bailey KR., and Pellikka PA.. Relationship Between Low Bone Mineral Density and Exercise-Induced Myocardial Ischemia. Mayo Clin. Proc., Jun 2007; 82: 679-685
21 Sormaala MJ, Niva MH, Kiuru MJ, Mattila VM, Pihlajamaki HK. Bone stress injuries of the talus in military recruits. Bone 2006;39:199-204
22 Otter MW, Qin YX, Rubin CT, McLeod KJ. Does bone perfusion/reperfusion initiate bone remodeling and the stress fracture syndrome? Med Hypotheses 1999;53:363-8
23 Zanetti M, Bruder E, Romero J, Hodler J. Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings. Radiology 2000;215:835-40
24 Plenk H Jr, Hofmann S, Eschberger J et al. Histomorphology and bone morphometry of the bone marrow edema syndrome of the hip. Clin Orthop Relat Res 1997;334:73-84
25 Imhof H, Sulzbacher I, Grampp S, Czerny C, Youssefzadeh S, Kainberger F. Subchondral bone and cartilage disease: a rediscovered functional unit. Invest Radiol 2000;35:581-8
26 Malinin T, Ouellette EA. Articular cartilage nutrition is mediated by subchondral bone: a long-term autograft study in baboons. OsteoarthrCartilage 2000;8:483-91
27 Sanchez C, Deberg MA, Piccardi N, Msika P, Reginster JY, Henrotin YE. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthr Cartilage 2005;13:988-97
28 Berger CE, Kroner AH, Minai-Pour MB, Ogris E, Engel A. Biochemical markers of bone metabolism in bone marrow edema syndrome of the hip. Bone 2003;33:346-51
29 Macfarlane DG, Buckland-Wright JC, Lynch J, Fogelman I. A study of the early and late 99technetium scintigraphic images and their relationship to symptoms in osteoarthritis of the hands. Br J Rheumatol 1993;32:977-81
30 Hayami T, Pickarski M, Zhuo Y, Wesolowski GA, Rodan GA, Duong le T. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone 2006;38:234-43
31 Hayami T, Pickarski M, Wesolowski GA et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transaction model. Arthritis Rheum 2004;50:1193-206
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2 Madsen JE, Hukkanen M, Aspenberg P, et al. Time-dependent sensory nerve ingrowth into a bone conduction chamber. Acta Orthop Scand 2000, 71:74-79
3 Embree MC, Kilts TM, Ono M, et al. Biglycan and fibromodulin have essential roles in regulating chondrogenesis and extracellular matrix turnover in temporomandibular joint osteoarthritis. Am J Pathol 2010, 176: 812-826
4 Mapp PI, Walsh DA, Bowyer J, Maciewicz RA. Effects of a metalloproteinase inhibitor on osteochondral angiogenesis, chondropathy and pain behavior in a rat model of osteoarthritis. Osteoarthritis Cartilage 2010, 18:593-600
5 Li A, Zhang Y, Lao L, at al. Serotonin receptor 2A/C is involved in electroacupuncture inhibition of pain in an osteoarthritis rat model. eCAM 2010, doi:10.1093/ecam/neq016
6 Shinoda Y, Ogata N, Higashikawa A, et al. Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9. J Biol Chem, 2008, 283(36): 24682-24689
1 Chen KH, Guo X, Ma D, et al. Dysregulation of HSG triggers vascular proliferative disorders [J]. Nature Cell Biol, 2004; 6: 872-83
2 Wang C, Han M, Zhao XM, Wen JK. Krüppel-like factor 4 is required for the expression of vascular smooth muscle cell differentiation marker genes induced by all-trans retinoic acid [J]. J Biochem, 2008, 144, 313-21
3 Shields JM, Christy RJ, Yang VW. Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem, 1996, 271(33): 20009-20017
4 Dang DT, Mahatan CS, Dang LH, et al. Expression of the gut-enriched kruppel-like factor (kruppel-like factor 4) gene in the human colon cancer cell line RKO is dependent on C DX2. Oncogene, 2001, 20(35): 4884-4890
5温进坤,韩梅.医学分子生物学理论与研究技术[M],北京:科学出版社,2001:296-7
1 Felson DT, Chaisson CE, Hill CL et al. The association of bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med 2001;134:541-9
2 YASUSHI AKAMATSU, NAOTO MITSUGI, NAOYA TAKI, RYOHEI TAKEUCHI, and TOMOYUKI SAITO. Relationship Between Low Bone Mineral Density and Varus Deformity in Postmenopausal Women with Knee Osteoarthritis .J Rheumatol Mar 2009; 36: 592-597
3 Jarvholm B, From C, Lewold S, Malchau H, and Ving?rd E. Incidence of surgically treated osteoarthritis in the hip and knee in male construction workers. Occup. Environ. Med., Apr 2008; 65: 275-278
4 Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 2001;286:188-95
5 Spector TD, MacGregor AJ. Risk factors for osteoarthritis: genetics. Osteoarthr Cartilage 2004;12(Suppl A):S39-44
6 Brandi ML, Collin-Osdoby P. Vascular biology and the skeleton. J Bone Miner Res 2006;21:183-92
7 Compston JE. Bone marrow and bone: a functional unit. J Endocrinol 2002;173:387-94
8 Satoru Otsuru, Katsuto Tamai, Takehiko Yamazaki, Hideki Yoshikawa, and Yasufumi Kaneda. Circulating Bone Marrow-Derived Osteoblast Progenitor Cells Are Recruited to the Bone-Forming Site by the CXCR4/Stromal Cell-Derived Factor-1 Pathway. Stem Cells, Jan 2008; 26: 223-234
9 Johnson EO, Soultanis K, Soucacos PN. Vascular anatomy and microcirculation of skeletal zones vulnerable to osteonecrosis: vascularization of the femoral head. Orthop Clin North Am 2004;35:285-91
10 Cowin SC. The plumbing of bone. In: Cerrolaza M, Mart?′nez G, Doblare′M, Calvo B, eds. Computational bioengineering: current trends and applications. World Scientific Publishing (UK): Imperial College Press, 2004;41-59
11 Imhof H, Breitenseher M, Kainberger F, Trattnig S. Degenerative joint disease: cartilage or vascular disease? Skeletal Radiol 1997;26:398-403
12 Reeve J, Arlot M, Wootton R et al. Skeletal blood flow, iliac histomorphometry, and strontium kinetics in osteoporosis: a relationship between blood flow and corrected apposition rate. J Clin Endocrinol Metab 1988;66:1124-31
13 Boraiah S., Dyke J. P., Hettrich C., Parker R. J., Miller A., Helfet D., and Lorich D.. Assessment of vascularity of the femoral head using gadolinium (Gd-DTPA)-enhanced magnetic resonance imaging: A CADAVER STUDY. J Bone Joint Surg Br; Jan 2009; 91-B: 131-137
14 Seeman E. Osteocytes-martyrs for integrity of bone strength. Osteoporos Int 2006;17:1443-8
15 You LD, Weinbaum S, Cowin SC, Schaffler MB. Ultrastructure of the osteocyte process and its pericellular matrix. Anat Rec a Discov Mol Cell Evol Biol 2004;278:505-13
16 Noble B. Microdamage and apoptosis. Eur J Morphol 2005;42:91–8. 24 Winkler DG, Sutherland MK, Geoghegan JC et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003;22:6267-76
17 Winkler DG, Sutherland MK, Geoghegan JC et al. Osteocyte controlof bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003;22:6267-76
18 Feng JQ, Ward LM, Liu S et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006;38:1310-5
19 Carrino JA, Blum J, Parellada JA, Schweitzer ME, Morrison WB. MRI of bone marrow edema-like signal in the pathogenesis of subchondral cysts. Osteoarthritis Cartilage 2006;14:1081-5
20 From AM., Hyder JA., Kearns AE., Bailey KR., and Pellikka PA.. Relationship Between Low Bone Mineral Density and Exercise-Induced Myocardial Ischemia. Mayo Clin. Proc., Jun 2007; 82: 679-685
21 Sormaala MJ, Niva MH, Kiuru MJ, Mattila VM, Pihlajamaki HK. Bone stress injuries of the talus in military recruits. Bone 2006;39:199-204
22 Otter MW, Qin YX, Rubin CT, McLeod KJ. Does bone perfusion/reperfusion initiate bone remodeling and the stress fracture syndrome? Med Hypotheses 1999;53:363-8
23 Zanetti M, Bruder E, Romero J, Hodler J. Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings. Radiology 2000;215:835-40
24 Plenk H Jr, Hofmann S, Eschberger J et al. Histomorphology and bone morphometry of the bone marrow edema syndrome of the hip. Clin Orthop Relat Res 1997;334:73-84
25 Imhof H, Sulzbacher I, Grampp S, Czerny C, Youssefzadeh S, Kainberger F. Subchondral bone and cartilage disease: a rediscovered functional unit. Invest Radiol 2000;35:581-8
26 Malinin T, Ouellette EA. Articular cartilage nutrition is mediated by subchondral bone: a long-term autograft study in baboons. OsteoarthrCartilage 2000;8:483-91
27 Sanchez C, Deberg MA, Piccardi N, Msika P, Reginster JY, Henrotin YE. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthr Cartilage 2005;13:988-97
28 Berger CE, Kroner AH, Minai-Pour MB, Ogris E, Engel A. Biochemical markers of bone metabolism in bone marrow edema syndrome of the hip. Bone 2003;33:346-51
29 Macfarlane DG, Buckland-Wright JC, Lynch J, Fogelman I. A study of the early and late 99technetium scintigraphic images and their relationship to symptoms in osteoarthritis of the hands. Br J Rheumatol 1993;32:977-81
30 Hayami T, Pickarski M, Zhuo Y, Wesolowski GA, Rodan GA, Duong le T. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone 2006;38:234-43
31 Hayami T, Pickarski M, Wesolowski GA et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transaction model. Arthritis Rheum 2004;50:1193-206
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