软骨前体细胞及微小RNA-140在骨关节炎软骨损伤修复中的作用
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摘要
目的总结软骨前体细胞(cartilage progenitor cells,CPCs)及微小RNA-140(microRNA-140,miR-140)在骨关节炎(osteoarthritis,OA)软骨损伤修复中的作用及应用前景。方法查阅国内外近年有关CPCs、miR-140及OA软骨损伤修复的相关研究,归纳总结后进行综述。结果 CPCs具有良好的自我增殖性、干细胞表面抗原表达特性及多向分化潜能等特点,其成软骨分化能力优于其他组织来源MSCs。CPCs与OA发生发展密切相关,但其在OA软骨损伤部位自主活化及成软骨分化能力方面并不能达到软骨完全修复的要求。miR-140具有软骨特异性,参与OA发病机制,具有抑制Notch信号通路、诱导活化CPCs并增强其增殖及成软骨分化的能力,从而促进OA软骨损伤修复的潜能。关节腔局部给药是目前治疗OA的主要方式之一,关节腔注射miR-140虽然对大鼠软骨退变具有显著抑制作用,但也存在非靶向聚集、生物利用度低及清除快等问题,基于关节软骨特性构建具有良好安全性、软骨靶向性且能高效递送miR-140的载体材料具有良好应用前景。此外,CPCs主要分散在软骨表层,而OA软骨损伤也开始于该层,因此强调OA早期干预至关重要。结论 miR-140具有诱导活化CPCs、促进OA早期软骨损伤修复的潜能,进一步探索miR-140在OA发生机制中的作用及研发基于miR-140的新的OA治疗策略具有重要临床意义。
Objective To summarize the effect of cartilage progenitor cells(CPCs) and microRNA-140(miR-140) on the repair of osteoarthritic cartilage injury, and analyze their clinical prospects. Methods The recent researches regarding the CPCs, miR-140, and repair of cartilage in osteoarthritis(OA) disease were extensively reviewed and summarized. Results CPCs possess the characteristics of self-proliferation, expression of stem cell markers, and multilineage differentiation potential, and their chondrogenic ability is superior to other tissues-derived mesenchymal stem cells. CPCs are closely related to the development of OA, but the autonomic activation and chondrogenic ability of CPCs around the osteoarthritic cartilage lesion cannot meet the requirements of complete cartilage repair. miR-140 specifically express in cartilage, and has the potential to activate CPCs by inhibiting key molecules of Notch signaling pathway and enhance its chondrogenic ability, thus promoting the repair of osteoarthritic cartilage injury. Intra-articular delivery of drugs is one of the main methods of OA treatment, although intra-articular injection of miR-140 has a significant inhibitory effect on cartilage degeneration in rats, it also exhibit some limitations such as non-targeted aggregation, low bioavailability, and rapid clearance. So it is a good application prospect to construct a carrier with good safety, cartilage targeting, and high-efficiency for miR-140 based on articular cartilage characteristics. In addition, CPCs are mainly dispersed in the cartilage surface, while OA cartilage injury also begins from this layer, it is therefore essential to emphasize early intervention of OA. Conclusion miR-140 has the potential to activate CPCs and promote the repair of cartilage injury in early OA, and it is of great clinical significance to further explore the role of miR-140 in OA etiology and to develop new OA treatment strategies based on miR-140.
Objective To summarize the effect of cartilage progenitor cells(CPCs) and microRNA-140(miR-140) on the repair of osteoarthritic cartilage injury, and analyze their clinical prospects. Methods The recent researches regarding the CPCs, miR-140, and repair of cartilage in osteoarthritis(OA) disease were extensively reviewed and summarized. Results CPCs possess the characteristics of self-proliferation, expression of stem cell markers, and multilineage differentiation potential, and their chondrogenic ability is superior to other tissues-derived mesenchymal stem cells. CPCs are closely related to the development of OA, but the autonomic activation and chondrogenic ability of CPCs around the osteoarthritic cartilage lesion cannot meet the requirements of complete cartilage repair. miR-140 specifically express in cartilage, and has the potential to activate CPCs by inhibiting key molecules of Notch signaling pathway and enhance its chondrogenic ability, thus promoting the repair of osteoarthritic cartilage injury. Intra-articular delivery of drugs is one of the main methods of OA treatment, although intra-articular injection of miR-140 has a significant inhibitory effect on cartilage degeneration in rats, it also exhibit some limitations such as non-targeted aggregation, low bioavailability, and rapid clearance. So it is a good application prospect to construct a carrier with good safety, cartilage targeting, and high-efficiency for miR-140 based on articular cartilage characteristics. In addition, CPCs are mainly dispersed in the cartilage surface, while OA cartilage injury also begins from this layer, it is therefore essential to emphasize early intervention of OA. Conclusion miR-140 has the potential to activate CPCs and promote the repair of cartilage injury in early OA, and it is of great clinical significance to further explore the role of miR-140 in OA etiology and to develop new OA treatment strategies based on miR-140.
引文
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8 Chen D, Shen J, Zhao W, et al. Osteoarthritis:toward a comprehensive understanding of pathological mechanism. Bone Res, 2017, 5:16044.
9 Lee WY, Wang B. Cartilage repair by mesenchymal stem cells:Clinical trial update and perspectives. J Orthop Translat, 2017, 9:76-88.
10 Li CY, Wu XY, Tong JB, et al. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res Ther,2015,6:55.
11符培亮,丛锐军,陈松,等.滑膜间充质干细胞成纤维软骨分化条件初步探索.中国修复重建外科杂志,2015, 29(1):81-91.
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13 Confalonieri D, Schwab A, Walles H, et al. Advanced therapy medicinal products:a guide for bone marrow-derived MSC application in bone and cartilage tissue engineering. Tissue Eng Part B Rev, 2018, 24(2):155-169.
14 Goldberg A, Mitchell K, Soans J, et al. The use of mesenchymal stem cells for cartilage repair and regeneration:a systematic review.J Orthop Surg Res, 2017, 12(1):39.
15 Barbero A, Ploegert S, Heberer M, et al. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum, 2003, 48(5):1315-1325.
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18 Jiang Y, Cai Y, Zhang W, et al. Human cartilage-derived progenitor cells from committed chondrocytes for efficient cartilage repair and regeneration. Stem Cells Transl Med, 2016, 5(6):733-744.
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25 McCarthy HE, Bara JJ, Brakspear K, et al. The comparison of equine articular cartilage progenitor cells and bone marrowderived stromal cells as potential cell sources for cartilage repair in the horse. Vet J, 2012,192(3):345-351.
26 Tao T, Li Y, Gui C, et al. Fibronectin enhances cartilage repair by activating progenitor cells through integrinα5β1 receptor. Int J Mol Sci, 2018, 24(13-14):1112-1124.
27 Borakati A, Mafi R, Mafi P, et al. A systematic review and metaanalysis of clinical trials of mesenchymal stem cell therapy for cartilage repair. Curr Stem Cell Res Ther, 2018,13(3):215-225.
28 Kumar H, Ha DH, Lee EJ, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain:1-year follow-up of a phaseⅠstudy. Stem Cell Res Ther, 2017, 8(1):262.
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30 Togo T, Utani A, Naitoh M, et al. Identification of cartilage progenitor cells in the adult ear perichondrium:utilization for cartilage reconstruction. Lab Invest, 2006, 86(5):445-457.
31 Takebe T, Kobayashi S, Kan H, et al. Human elastic cartilage engineering from cartilage progenitor cells using rotating wall vessel bioreactor. Transplant Proc, 2012,44(4):1158-1161.
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34 Araldi E, Schipani E. MicroRNA-140 and the silencing of osteoarthritis. Genes Dev, 2010, 24(11):1075-1080.
35 Miyaki S, Nakasa T, Otsuki S, et al. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum, 2009, 60(9):2723-2730.
36 Swingler TE, Wheeler G, Carmont V, et al. The expression and function of microRNAs in chondrogenesis and osteoarthritis.Arthritis Rheum, 2012, 64(6):1909-1919.
37张明,刘立宏,肖涛,等.实时荧光定量PCR检测骨性关节病人膝关节液中miR-140的表达.中南大学学报(医学版),2012,37(12):1210-1214.
38 Si HB, Zeng Y, Liu SY, et al. Intra-articular injection of microRNA-140(miRNA-140)alleviates osteoarthritis(OA)progression by modulating extracellular matrix(ECM)homeostasis in rats.Osteoarthritis Cartilage, 2017, 25(10):1698-1707.
39 Si H, Zeng Y, Zhou Z, et al. Expression of miRNA-140 in chondrocytes and synovial fluid of knee joints in patients with osteoarthritis. Chin Med Sci J, 2016, 31(4):207-212.
40 Papaioannou G, Mirzamohammadi F, Lisse TS, et al. MicroRNA-140 provides robustness to the regulation of hypertrophic chondrocyte differentiation by the PTHrP-HDAC4 pathway. J Bone Miner Res, 2015, 30(6):1044-1052.
41张洋洋,彭效祥,宋伟,等.核定位信号肽偶联核激酶底物短肽修饰壳聚糖介导微小RNA-140对兔关节软骨细胞作用的研究.中国修复重建外科杂志,2017, 31(10):1256-1261.
42 Hossein M, Masoud S, Hana HA, et al. New approach for differentiation of bone marrow mesenchymal stem cells toward chondrocyte cells with overexpression of microRNA-140. ASAIO J,2018, 64(5):662-672.
43 Cao Z, Liu C, Bai Y, et al. Inhibitory effect of dihydroartemisinin on chondrogenic and hypertrophic differentiation of mesenchymal stem cells. Am J Transl Res, 2017, 9(6):2748-2759.
44 Grogan SP, Miyaki S, Asahara H, et al. Mesenchymal progenitor cell markers in human articular cartilage:normal distribution and changes in osteoarthritis. Arthritis Res Ther, 2009, 11(3):R85.
45 Li F, Shi W, Wan Y, et al. Prediction of target genes for miR-140-5p in pulmonary arterial hypertension using bioinformatics methods.FEBS Open Bio, 2017, 7(12):1880-1890.
46 Khayrullin A, Smith L, Mistry D, et al. Chronic alcohol exposure induces muscle atrophy(myopathy)in zebrafish and alters the expression of microRNAs targeting the Notch pathway in skeletal muscle. Biochem Biophys Res Commun, 2016,479(3):590-595.
47杨体敏,斯海波,吴元刚,等.收肌管神经阻滞联合环氧合酶2选择性抑制剂在人工全膝关节置换术后的序贯应用及疗效.中国修复重建外科杂志,2016, 30(9):1065-1071.
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2 Park YB, Ha CW, Rhim JH, et al. Stem cell therapy for articular cartilage repair:review of the entity of cell populations used and the result of the clinical application of each entity. Am J Sports Med, 2018, 46(10):2540-2552.
3 McGonagle D, Baboolal TG, Jones E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nat Rev Rheumatol, 2017,13(12):719-730.
4 Zhang R, Ma J, Yao J. Molecular mechanisms of the cartilage-specific microRNA-140 in osteoarthritis. Inflamm Res, 2013,62(10):871-877.
5 Miyaki S, Sato T, Inoue A, et al. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev, 2010,24(11):1173-1185.
6陈蓟,雷鸣,刘弼,等.MicroRNA与骨关节炎.中国矫形外科杂志,2017, 25(19):1783-1787.
7 Mahboudi H, Soleimani M, Enderami SE, et al. Enhanced chondrogenesis differentiation of human induced pluripotent stem cells by MicroRNA-140 and transforming growth factor beta 3(TGF(33). Biologicals, 2018, 52:30-36.
8 Chen D, Shen J, Zhao W, et al. Osteoarthritis:toward a comprehensive understanding of pathological mechanism. Bone Res, 2017, 5:16044.
9 Lee WY, Wang B. Cartilage repair by mesenchymal stem cells:Clinical trial update and perspectives. J Orthop Translat, 2017, 9:76-88.
10 Li CY, Wu XY, Tong JB, et al. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res Ther,2015,6:55.
11符培亮,丛锐军,陈松,等.滑膜间充质干细胞成纤维软骨分化条件初步探索.中国修复重建外科杂志,2015, 29(1):81-91.
12张金丽,刘志河,汤文彬,等.大鼠脂肪来源干细胞对紫外线造成的软骨细胞DNA损伤的修复作用研究.中国修复重建外科杂志,2017, 31(5):600-606.
13 Confalonieri D, Schwab A, Walles H, et al. Advanced therapy medicinal products:a guide for bone marrow-derived MSC application in bone and cartilage tissue engineering. Tissue Eng Part B Rev, 2018, 24(2):155-169.
14 Goldberg A, Mitchell K, Soans J, et al. The use of mesenchymal stem cells for cartilage repair and regeneration:a systematic review.J Orthop Surg Res, 2017, 12(1):39.
15 Barbero A, Ploegert S, Heberer M, et al. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum, 2003, 48(5):1315-1325.
16 Mantripragada VP, Bova WA, Boehm C, et al. Progenitor cells from different zones of human cartilage and their correlation with histopathological osteoarthritis progression. J Orthop Res, 2018,38(6):1728-1738.
17周建新,杨晓斐,李阳,等.软骨前体细胞的分离鉴定及IL-1β对其成软骨分化的影响.中国修复重建外科杂志,2015, 29(7):863-869.
18 Jiang Y, Cai Y, Zhang W, et al. Human cartilage-derived progenitor cells from committed chondrocytes for efficient cartilage repair and regeneration. Stem Cells Transl Med, 2016, 5(6):733-744.
19 Galipeau J, Krampera M, Barrett J, et al. International society for cellular therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy, 2016, 18(2):151-159.
20 Pretzel D, Linss S, Rochler S, et al. Relative percentage and zonal distribution of mesenchymal progenitor cells in human osteoarthritic and normal cartilage. Arthritis Res Ther, 2011, 13(2):R64.
21 Alsalameh S, Amin R, Gemba T, et al. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum, 2004, 50(5):1522-1532.
22 Mazor M, Cesaro A, Ali M, et al. Progenitor cells from cartilage:grade specific differences in stem cell marker expression. Int J Mol Sci,2017,18(8):E1759.
23 Xia Z, Ma P, Wu N, et al. Altered function in cartilage derived mesenchymal stem cell leads to OA-related cartilage erosion. Am J Transl Res, 2016, 8(2):433-446.
24 Seol D, McCabe DJ, Choe H, et al. Chondrogenic progenitor cells respond to cartilage injury. Arthritis Rheum, 2012, 64(11):3626-3637.
25 McCarthy HE, Bara JJ, Brakspear K, et al. The comparison of equine articular cartilage progenitor cells and bone marrowderived stromal cells as potential cell sources for cartilage repair in the horse. Vet J, 2012,192(3):345-351.
26 Tao T, Li Y, Gui C, et al. Fibronectin enhances cartilage repair by activating progenitor cells through integrinα5β1 receptor. Int J Mol Sci, 2018, 24(13-14):1112-1124.
27 Borakati A, Mafi R, Mafi P, et al. A systematic review and metaanalysis of clinical trials of mesenchymal stem cell therapy for cartilage repair. Curr Stem Cell Res Ther, 2018,13(3):215-225.
28 Kumar H, Ha DH, Lee EJ, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain:1-year follow-up of a phaseⅠstudy. Stem Cell Res Ther, 2017, 8(1):262.
29 Al-Najar M, Khalil H, Al-Ajlouni J, et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe:a phaseⅠ/Ⅱstudy. J Orthop Surg Res, 2017,12(1):190.
30 Togo T, Utani A, Naitoh M, et al. Identification of cartilage progenitor cells in the adult ear perichondrium:utilization for cartilage reconstruction. Lab Invest, 2006, 86(5):445-457.
31 Takebe T, Kobayashi S, Kan H, et al. Human elastic cartilage engineering from cartilage progenitor cells using rotating wall vessel bioreactor. Transplant Proc, 2012,44(4):1158-1161.
32 Nugent M. MicroRNAs:exploring new horizons in osteoarthritis.Osteoarthritis Cartilage, 2016, 24(4):573-580.
33冀全博,徐亚梦,王岩.miRNA与骨关节炎软骨基质降解的研究进展.中国修复重建外科杂志,2016, 30(11):1431-1436.
34 Araldi E, Schipani E. MicroRNA-140 and the silencing of osteoarthritis. Genes Dev, 2010, 24(11):1075-1080.
35 Miyaki S, Nakasa T, Otsuki S, et al. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum, 2009, 60(9):2723-2730.
36 Swingler TE, Wheeler G, Carmont V, et al. The expression and function of microRNAs in chondrogenesis and osteoarthritis.Arthritis Rheum, 2012, 64(6):1909-1919.
37张明,刘立宏,肖涛,等.实时荧光定量PCR检测骨性关节病人膝关节液中miR-140的表达.中南大学学报(医学版),2012,37(12):1210-1214.
38 Si HB, Zeng Y, Liu SY, et al. Intra-articular injection of microRNA-140(miRNA-140)alleviates osteoarthritis(OA)progression by modulating extracellular matrix(ECM)homeostasis in rats.Osteoarthritis Cartilage, 2017, 25(10):1698-1707.
39 Si H, Zeng Y, Zhou Z, et al. Expression of miRNA-140 in chondrocytes and synovial fluid of knee joints in patients with osteoarthritis. Chin Med Sci J, 2016, 31(4):207-212.
40 Papaioannou G, Mirzamohammadi F, Lisse TS, et al. MicroRNA-140 provides robustness to the regulation of hypertrophic chondrocyte differentiation by the PTHrP-HDAC4 pathway. J Bone Miner Res, 2015, 30(6):1044-1052.
41张洋洋,彭效祥,宋伟,等.核定位信号肽偶联核激酶底物短肽修饰壳聚糖介导微小RNA-140对兔关节软骨细胞作用的研究.中国修复重建外科杂志,2017, 31(10):1256-1261.
42 Hossein M, Masoud S, Hana HA, et al. New approach for differentiation of bone marrow mesenchymal stem cells toward chondrocyte cells with overexpression of microRNA-140. ASAIO J,2018, 64(5):662-672.
43 Cao Z, Liu C, Bai Y, et al. Inhibitory effect of dihydroartemisinin on chondrogenic and hypertrophic differentiation of mesenchymal stem cells. Am J Transl Res, 2017, 9(6):2748-2759.
44 Grogan SP, Miyaki S, Asahara H, et al. Mesenchymal progenitor cell markers in human articular cartilage:normal distribution and changes in osteoarthritis. Arthritis Res Ther, 2009, 11(3):R85.
45 Li F, Shi W, Wan Y, et al. Prediction of target genes for miR-140-5p in pulmonary arterial hypertension using bioinformatics methods.FEBS Open Bio, 2017, 7(12):1880-1890.
46 Khayrullin A, Smith L, Mistry D, et al. Chronic alcohol exposure induces muscle atrophy(myopathy)in zebrafish and alters the expression of microRNAs targeting the Notch pathway in skeletal muscle. Biochem Biophys Res Commun, 2016,479(3):590-595.
47杨体敏,斯海波,吴元刚,等.收肌管神经阻滞联合环氧合酶2选择性抑制剂在人工全膝关节置换术后的序贯应用及疗效.中国修复重建外科杂志,2016, 30(9):1065-1071.
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