细胞自噬与肌腱病的靶向自噬途径
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摘要
背景:肌腱是一种连接骨骼和肌肉的纤维组织,主要功能是在运动时从肌肉向骨骼传导应力,肌腱病是临床常见的疾病类型,表现为肌腱炎症、退变和损伤。细胞自噬广泛参与许多疾病的发展。基于细胞自噬的研究方法为肌腱损伤的修复提供了新的思路。目的:综述细胞自噬的发生过程和调控机制,分析细胞自噬参与肌腱病的病理机制,为肌腱病的预防治疗提供参考。方法:应用计算机检索中国知网、万方数据库及PubMed数据库关于自噬与肌腱病的相关研究的文章,中文检索词为"自噬、肌腱、成纤维细胞、肌腱病",英文检索词为"autophagy,tendon,fibroblast,tendinopathy"。进行系统的归纳总结和分析,排除内容相关性差或重复文献,最终得到54篇文献。结果与结论:自噬可以减轻氧化应激对人肌腱干细胞的损害;随着肌腱组织的细胞外基质降解程度的增加,肌腱细胞由于过度的细胞自噬出现自噬性细胞死亡;前列腺素E2以剂量依赖的方式显著诱导成纤维细胞的死亡和自噬;肩袖损伤后的肌肉萎缩受自噬调控;雷帕霉素通过自噬的激活抑制肌腱损伤后的腱周纤维化。综合目前研究结果,自噬在肌腱病中有重要作用,自噬将会成为肌腱病新的研究热点,更加详细地了解自噬过程及其在肌腱病中的作用,有助于研究人员找到肌腱病的靶向自噬途径,为干预和治疗肌腱病提供新的理论和方法支持。
BACKGROUND: Tendon is a fibrous tissue that connects bone and muscle. The main function is to conduct stress from the muscles to the bone during exercise. Tendinopathy is a commonly seen disease, characterized by tendon inflammation, degeneration and injury. Autophagy is widely involved in the development of many degenerative diseases. The research method based on autophagy provides a new idea for tendon repair. OBJECTIVE: To review the process and regulation mechanism of autophagy, and to analyze the pathological mechanism of autophagy involved in the tendinopathy so as to provide a reference for the prevention and treatment of tendinopathy. METHODS: The articles concerning autophagy and tendinopathy were retrieved by computer in CNKI, WanFang and PubMed databases. The keywords were "autophagy, tendon, fibroblast, tendinopathy" in English and Chinese, respectively. Finally, 54 articles were obtained through systematic induction and analysis after excluding the irrelevant and repetitive articles. RESULTS AND CONCLUSION: Autophagy can alleviate the damage to human tendon stem cells induced by oxidative stress. With the increase of the degree of extracellular matrix degradation in the tendon tissue, autophagic cell death occurs in the tendon cells due to excessive autophagy. Prostaglandin E2 significantly induces fibroblast death and autophagy in a dose-dependent manner. The muscle atrophy after the rotator cuff injury is regulated by autophagy. Rapamycin prevents peritendinous fibrosis through activation of autophagy. In conclusion, autophagy plays an important role in tendinopathy. Autophagy will become a new hotspot in tendinopathy. Further understanding of autophagy and its role in tendinopathy will contribute to finding a targeted autophagy pathway and provide new theoretical and methodological support for the intervention and treatment of tendinopathy.
BACKGROUND: Tendon is a fibrous tissue that connects bone and muscle. The main function is to conduct stress from the muscles to the bone during exercise. Tendinopathy is a commonly seen disease, characterized by tendon inflammation, degeneration and injury. Autophagy is widely involved in the development of many degenerative diseases. The research method based on autophagy provides a new idea for tendon repair. OBJECTIVE: To review the process and regulation mechanism of autophagy, and to analyze the pathological mechanism of autophagy involved in the tendinopathy so as to provide a reference for the prevention and treatment of tendinopathy. METHODS: The articles concerning autophagy and tendinopathy were retrieved by computer in CNKI, WanFang and PubMed databases. The keywords were "autophagy, tendon, fibroblast, tendinopathy" in English and Chinese, respectively. Finally, 54 articles were obtained through systematic induction and analysis after excluding the irrelevant and repetitive articles. RESULTS AND CONCLUSION: Autophagy can alleviate the damage to human tendon stem cells induced by oxidative stress. With the increase of the degree of extracellular matrix degradation in the tendon tissue, autophagic cell death occurs in the tendon cells due to excessive autophagy. Prostaglandin E2 significantly induces fibroblast death and autophagy in a dose-dependent manner. The muscle atrophy after the rotator cuff injury is regulated by autophagy. Rapamycin prevents peritendinous fibrosis through activation of autophagy. In conclusion, autophagy plays an important role in tendinopathy. Autophagy will become a new hotspot in tendinopathy. Further understanding of autophagy and its role in tendinopathy will contribute to finding a targeted autophagy pathway and provide new theoretical and methodological support for the intervention and treatment of tendinopathy.
引文
[1]Nourissat G,Berenbaum F,Duprez D.Tendon injury:from biology to tendon repair.Nat Rev Rheumatol.2015;11(4):223-233.
[2]Takeshige K,Baba M,Tsuboi S,et al.Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction.J Cell Biol.1992;119(2):301-311.
[3]Kim KH,Lee MS.Autophagy-a key player in cellular and body metabolism.Nat Rev Endocrinol.2014;10(6):322-337.
[4]Feng Y,He D,Yao Z,et al.The machinery of macroautophagy.Cell Res.2014;24(1):24-41.
[5]Duarte JH.Osteoarthritis:autophagy prevents age-related OA.Nat Rev Rheumatol.2015;11(12):683.
[6]Genevini P,Papiani G,Ruggiano A,et al.Amyotrophic lateral sclerosis-linked mutant VAPB inclusions do not interfere with protein degradation pathways or intracellular transport in a cultured cell model.PLoS One.2014;9(11):e113416.
[7]Kadow T,Sowa G,Vo N,et al.Molecular basis of intervertebral disc degeneration and herniations:what are the important translational questions?Clin Orthop Relat Res.2015;473(6):1903-1912.
[8]Hosokawa N,Hara T,Kaizuka T,et al.Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200complex required for autophagy.Mol Biol Cell.2009;20(7):1981-1991.
[9]Itakura E,Kishi C,Inoue K,et al.Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG.Mol Biol Cell.2008;19(12):5360-5372.
[10]Liang C,Lee J S,Inn K S,et al.Beclin1-binding UVRAGtargets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking.Nat Cell Biol.2008;10(7):776-787.
[11]Matsunaga K,Saitoh T,Tabata K,et al.Two Beclin 1-binding proteins,Atg14L and Rubicon,reciprocally regulate autophagy at different stages.Nat Cell Biol.2009;11(4):385-396.
[12]He C,Klionsky DJ.Regulation mechanisms and signaling pathways of autophagy.Annu Rev Genet.2009;43:67-93.
[13]Luo P,Gao F,Han J,et al.The role of autophagy in steroid necrosis of the femoral head:a comprehensive research review.Int Orthop.2018;42(7):1747-1753.
[14]Kim J,Kundu M,Viollet B,et al.AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.Nat Cell Biol.2011;13(2):132-141.
[15]Simonsen A,Tooze S A.Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes.J Cell Biol.2009;186(6):773-782.
[16]Tasdemir E,Maiuri M C,Tajeddine N,et al.Cell cycle-dependent induction of autophagy,mitophagy and reticulophagy.Cell Cycle.2007;6(18):2263-2267.
[17]An Z,Tassa A,Thomas C,et al.Autophagy is required for G(1)/G(0)quiescence in response to nitrogen starvation in Saccharomyces cerevisiae.Autophagy.2014;10(10):1702-1711.
[18]Li H,Peng X,Wang Y,et al.Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis.Autophagy.2016;12(9):1472-1486.
[19]Martinet W,Agostinis P,Vanhoecke B,et al.Autophagy in disease:a double-edged sword with therapeutic potential.Clin Sci(Lond).2009;116(9):697-712.
[20]Shen HM,Codogno P.Autophagic cell death:loch ness monster or endangered species?Autophagy.2011;7(5):457-465.
[21]Ch'En IL,Beisner DR,Degterev A,et al.Antigen-mediated Tcell expansion regulated by parallel pathways of death.Proc Natl Acad Sci U S A.2008;105(45):17463-17468.
[22]Bell BD,Leverrier S,Weist BM,et al.FADD and caspase-8control the outcome of autophagic signaling in proliferating T cells.Proc Natl Acad Sci U S A.2008;105(43):16677-16682.
[23]Jain MV,Paczulla AM,Klonisch T,et al.Interconnections between apoptotic,autophagic and necrotic pathways:implications for cancer therapy development.J Cell Mol Med.2013;17(1):12-29.
[24]Yu L,Alva A,Su H,et al.Regulation of an ATG7-beclin 1program of autophagic cell death by caspase-8.Science.2004;304(5676):1500-1502.
[25]Gozuacik D,Kimchi A.Autophagy as a cell death and tumor suppressor mechanism.Oncogene.2004,23(16):2891-2906.
[26]Kroemer G,Levine B.Autophagic cell death:the story of a misnomer.Nat Rev Mol Cell Biol.2008;9(12):1004-1010.
[27]Xiong HY,Guo XL,Bu XX,et al.Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell.Cancer Lett.2010;288(1):68-74.
[28]Russell J E,Manske PR.Collagen synthesis during primate flexor tendon repair in vitro.J Orthop Res.1990;8(1):13-20.
[29]Ferraro E,Cecconi F.Autophagic and apoptotic response to stress signals in mammalian cells.Arch Biochem Biophys.2007;462(2):210-219.
[30]Wu B,Chen J,Dela R T,et al.Cellular response and extracellular matrix breakdown in rotator cuff tendon rupture.Arch Orthop Trauma Surg.2011;131(3):405-411.
[31]桂金鹏,江静怡,张灵玉,等.力学因素对细胞自噬的影响[J].中国组织工程研究,2017,21(12):1946-1952.
[32]Jeon H,Im GI.Autophagy in osteoarthritis.Connect Tissue Res.2017;58(6):497-508.
[33]刘利国,徐超,伊力哈木·托合提.自噬基因在骨关节炎软骨细胞凋亡过程中的保护和平衡效应[J].中国组织工程研究,2015,19(20):3231-3235.
[34]Ye W,Xu K,Huang D,et al.Age-related increases of macroautophagy and chaperone-mediated autophagy in rat nucleus pulposus.Connect Tissue Res.2011;52(6):472-478.
[35]Xu H,Xiong S,Wang H,et al.The evidence and the possible significance of autophagy in degeneration model of human cervical end-plate cartilage.Exp Ther Med.2014;7(3):537-542.
[36]Gruber HE,Hoelscher GL,Ingram JA,et al.Autophagy in the degenerating human intervertebral disc:in vivo molecular and morphological evidence,and induction of autophagy in cultured annulus cells exposed to proinflammatory cytokines-implications for disc degeneration.Spine(Phila Pa1976).2015;40(11):773-782.
[37]Onal M,Piemontese M,Xiong J,et al.Suppression of autophagy in osteocytes mimics skeletal aging.J Biol Chem.2013;288(24):17432-17440.
[38]Komatsu M,Waguri S,Chiba T,et al.Loss of autophagy in the central nervous system causes neurodegeneration in mice.Nature.2006;441(7095):880-884.
[39]Archambault JM,Wiley JP,Bray RC.Exercise loading of tendons and the development of overuse injuries.A review of current literature.Sports Med.1995;20(2):77-89.
[40]Yuan J,Murrell G A,Trickett A,et al.Involvement of cytochrome c release and caspase-3 activation in the oxidative stress-induced apoptosis in human tendon fibroblasts.Biochim Biophys Acta.2003;1641(1):35-41.
[41]Chen H,Ge HA,Wu GB,et al.Autophagy prevents oxidative stress-induced loss of self-renewal capacity and stemness in human tendon stem cells by reducing ROS accumulation.Cell Physiol Biochem.2016;39(6):2227-2238.
[42]Osti L,Buda M,Del BA,et al.Apoptosis and rotator cuff tears:scientific evidence from basic science to clinical findings.Br Med Bull.2017;122(1):123-133.
[43]Tuoheti Y,Itoi E,Pradhan R L,et al.Apoptosis in the supraspinatus tendon with stage II subacromial impingement.J Shoulder Elbow Surg.2005;14(5):535-541.
[44]Somers P,Knaapen M,Kockx M,et al.Histological evaluation of autophagic cell death in calcified aortic valve stenosis.JHeart Valve Dis.2006;15(1):43-48.
[45]Premdas J,Tang JB,Warner JP,et al.The presence of smooth muscle actin in fibroblasts in the torn human rotator cuff.J Orthop Res.2001;19(2):221-228.
[46]Chen J,Wang A,Xu J,et al.In chronic lateral epicondylitis,apoptosis and autophagic cell death occur in the extensor carpi radialis brevis tendon.J Shoulder Elbow Surg.2010;19(3):355-362.
[47]Meijer AJ,Codogno P.Signalling and autophagy regulation in health,aging and disease.Mol Aspects Med.2006;27(5-6):411-425.
[48]Khan MH,Li Z,Wang JH.Repeated exposure of tendon to prostaglandin-E2 leads to localized tendon degeneration.Clin J Sport Med.2005;15(1):27-33.
[49]Chen H,Chen L,Cheng B,et al.Cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of prostaglandin E2 production.Cell Physiol Biochem.2015;36(1):24-33.
[50]Yamaguchi K,Tetro AM,Blam O,et al.Natural history of asymptomatic rotator cuff tears:a longitudinal analysis of asymptomatic tears detected sonographically.J Shoulder Elbow Surg.2001;10(3):199-203.
[51]Albritton MJ,Graham RD,Richards RN,et al.An anatomic study of the effects on the suprascapular nerve due to retraction of the supraspinatus muscle after a rotator cuff tear.J Shoulder Elbow Surg.2003;12(5):497-500.
[52]Joshi SK,Kim HT,Feeley BT,et al.Differential ubiquitin-proteasome and autophagy signaling following rotator cuff tears and suprascapular nerve injury.J Orthop Res.2014;32(1):138-144.
[53]Wynn TA,Ramalingam TR.Mechanisms of fibrosis:therapeutic translation for fibrotic disease.Nat Med.2012;18(7):1028-1040.
[54]Zheng W,Qian Y,Chen S,et al.Rapamycin protects against peritendinous fibrosis through activation of autophagy.Front Pharmacol.2018;9:402.
[2]Takeshige K,Baba M,Tsuboi S,et al.Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction.J Cell Biol.1992;119(2):301-311.
[3]Kim KH,Lee MS.Autophagy-a key player in cellular and body metabolism.Nat Rev Endocrinol.2014;10(6):322-337.
[4]Feng Y,He D,Yao Z,et al.The machinery of macroautophagy.Cell Res.2014;24(1):24-41.
[5]Duarte JH.Osteoarthritis:autophagy prevents age-related OA.Nat Rev Rheumatol.2015;11(12):683.
[6]Genevini P,Papiani G,Ruggiano A,et al.Amyotrophic lateral sclerosis-linked mutant VAPB inclusions do not interfere with protein degradation pathways or intracellular transport in a cultured cell model.PLoS One.2014;9(11):e113416.
[7]Kadow T,Sowa G,Vo N,et al.Molecular basis of intervertebral disc degeneration and herniations:what are the important translational questions?Clin Orthop Relat Res.2015;473(6):1903-1912.
[8]Hosokawa N,Hara T,Kaizuka T,et al.Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200complex required for autophagy.Mol Biol Cell.2009;20(7):1981-1991.
[9]Itakura E,Kishi C,Inoue K,et al.Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG.Mol Biol Cell.2008;19(12):5360-5372.
[10]Liang C,Lee J S,Inn K S,et al.Beclin1-binding UVRAGtargets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking.Nat Cell Biol.2008;10(7):776-787.
[11]Matsunaga K,Saitoh T,Tabata K,et al.Two Beclin 1-binding proteins,Atg14L and Rubicon,reciprocally regulate autophagy at different stages.Nat Cell Biol.2009;11(4):385-396.
[12]He C,Klionsky DJ.Regulation mechanisms and signaling pathways of autophagy.Annu Rev Genet.2009;43:67-93.
[13]Luo P,Gao F,Han J,et al.The role of autophagy in steroid necrosis of the femoral head:a comprehensive research review.Int Orthop.2018;42(7):1747-1753.
[14]Kim J,Kundu M,Viollet B,et al.AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.Nat Cell Biol.2011;13(2):132-141.
[15]Simonsen A,Tooze S A.Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes.J Cell Biol.2009;186(6):773-782.
[16]Tasdemir E,Maiuri M C,Tajeddine N,et al.Cell cycle-dependent induction of autophagy,mitophagy and reticulophagy.Cell Cycle.2007;6(18):2263-2267.
[17]An Z,Tassa A,Thomas C,et al.Autophagy is required for G(1)/G(0)quiescence in response to nitrogen starvation in Saccharomyces cerevisiae.Autophagy.2014;10(10):1702-1711.
[18]Li H,Peng X,Wang Y,et al.Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis.Autophagy.2016;12(9):1472-1486.
[19]Martinet W,Agostinis P,Vanhoecke B,et al.Autophagy in disease:a double-edged sword with therapeutic potential.Clin Sci(Lond).2009;116(9):697-712.
[20]Shen HM,Codogno P.Autophagic cell death:loch ness monster or endangered species?Autophagy.2011;7(5):457-465.
[21]Ch'En IL,Beisner DR,Degterev A,et al.Antigen-mediated Tcell expansion regulated by parallel pathways of death.Proc Natl Acad Sci U S A.2008;105(45):17463-17468.
[22]Bell BD,Leverrier S,Weist BM,et al.FADD and caspase-8control the outcome of autophagic signaling in proliferating T cells.Proc Natl Acad Sci U S A.2008;105(43):16677-16682.
[23]Jain MV,Paczulla AM,Klonisch T,et al.Interconnections between apoptotic,autophagic and necrotic pathways:implications for cancer therapy development.J Cell Mol Med.2013;17(1):12-29.
[24]Yu L,Alva A,Su H,et al.Regulation of an ATG7-beclin 1program of autophagic cell death by caspase-8.Science.2004;304(5676):1500-1502.
[25]Gozuacik D,Kimchi A.Autophagy as a cell death and tumor suppressor mechanism.Oncogene.2004,23(16):2891-2906.
[26]Kroemer G,Levine B.Autophagic cell death:the story of a misnomer.Nat Rev Mol Cell Biol.2008;9(12):1004-1010.
[27]Xiong HY,Guo XL,Bu XX,et al.Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell.Cancer Lett.2010;288(1):68-74.
[28]Russell J E,Manske PR.Collagen synthesis during primate flexor tendon repair in vitro.J Orthop Res.1990;8(1):13-20.
[29]Ferraro E,Cecconi F.Autophagic and apoptotic response to stress signals in mammalian cells.Arch Biochem Biophys.2007;462(2):210-219.
[30]Wu B,Chen J,Dela R T,et al.Cellular response and extracellular matrix breakdown in rotator cuff tendon rupture.Arch Orthop Trauma Surg.2011;131(3):405-411.
[31]桂金鹏,江静怡,张灵玉,等.力学因素对细胞自噬的影响[J].中国组织工程研究,2017,21(12):1946-1952.
[32]Jeon H,Im GI.Autophagy in osteoarthritis.Connect Tissue Res.2017;58(6):497-508.
[33]刘利国,徐超,伊力哈木·托合提.自噬基因在骨关节炎软骨细胞凋亡过程中的保护和平衡效应[J].中国组织工程研究,2015,19(20):3231-3235.
[34]Ye W,Xu K,Huang D,et al.Age-related increases of macroautophagy and chaperone-mediated autophagy in rat nucleus pulposus.Connect Tissue Res.2011;52(6):472-478.
[35]Xu H,Xiong S,Wang H,et al.The evidence and the possible significance of autophagy in degeneration model of human cervical end-plate cartilage.Exp Ther Med.2014;7(3):537-542.
[36]Gruber HE,Hoelscher GL,Ingram JA,et al.Autophagy in the degenerating human intervertebral disc:in vivo molecular and morphological evidence,and induction of autophagy in cultured annulus cells exposed to proinflammatory cytokines-implications for disc degeneration.Spine(Phila Pa1976).2015;40(11):773-782.
[37]Onal M,Piemontese M,Xiong J,et al.Suppression of autophagy in osteocytes mimics skeletal aging.J Biol Chem.2013;288(24):17432-17440.
[38]Komatsu M,Waguri S,Chiba T,et al.Loss of autophagy in the central nervous system causes neurodegeneration in mice.Nature.2006;441(7095):880-884.
[39]Archambault JM,Wiley JP,Bray RC.Exercise loading of tendons and the development of overuse injuries.A review of current literature.Sports Med.1995;20(2):77-89.
[40]Yuan J,Murrell G A,Trickett A,et al.Involvement of cytochrome c release and caspase-3 activation in the oxidative stress-induced apoptosis in human tendon fibroblasts.Biochim Biophys Acta.2003;1641(1):35-41.
[41]Chen H,Ge HA,Wu GB,et al.Autophagy prevents oxidative stress-induced loss of self-renewal capacity and stemness in human tendon stem cells by reducing ROS accumulation.Cell Physiol Biochem.2016;39(6):2227-2238.
[42]Osti L,Buda M,Del BA,et al.Apoptosis and rotator cuff tears:scientific evidence from basic science to clinical findings.Br Med Bull.2017;122(1):123-133.
[43]Tuoheti Y,Itoi E,Pradhan R L,et al.Apoptosis in the supraspinatus tendon with stage II subacromial impingement.J Shoulder Elbow Surg.2005;14(5):535-541.
[44]Somers P,Knaapen M,Kockx M,et al.Histological evaluation of autophagic cell death in calcified aortic valve stenosis.JHeart Valve Dis.2006;15(1):43-48.
[45]Premdas J,Tang JB,Warner JP,et al.The presence of smooth muscle actin in fibroblasts in the torn human rotator cuff.J Orthop Res.2001;19(2):221-228.
[46]Chen J,Wang A,Xu J,et al.In chronic lateral epicondylitis,apoptosis and autophagic cell death occur in the extensor carpi radialis brevis tendon.J Shoulder Elbow Surg.2010;19(3):355-362.
[47]Meijer AJ,Codogno P.Signalling and autophagy regulation in health,aging and disease.Mol Aspects Med.2006;27(5-6):411-425.
[48]Khan MH,Li Z,Wang JH.Repeated exposure of tendon to prostaglandin-E2 leads to localized tendon degeneration.Clin J Sport Med.2005;15(1):27-33.
[49]Chen H,Chen L,Cheng B,et al.Cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of prostaglandin E2 production.Cell Physiol Biochem.2015;36(1):24-33.
[50]Yamaguchi K,Tetro AM,Blam O,et al.Natural history of asymptomatic rotator cuff tears:a longitudinal analysis of asymptomatic tears detected sonographically.J Shoulder Elbow Surg.2001;10(3):199-203.
[51]Albritton MJ,Graham RD,Richards RN,et al.An anatomic study of the effects on the suprascapular nerve due to retraction of the supraspinatus muscle after a rotator cuff tear.J Shoulder Elbow Surg.2003;12(5):497-500.
[52]Joshi SK,Kim HT,Feeley BT,et al.Differential ubiquitin-proteasome and autophagy signaling following rotator cuff tears and suprascapular nerve injury.J Orthop Res.2014;32(1):138-144.
[53]Wynn TA,Ramalingam TR.Mechanisms of fibrosis:therapeutic translation for fibrotic disease.Nat Med.2012;18(7):1028-1040.
[54]Zheng W,Qian Y,Chen S,et al.Rapamycin protects against peritendinous fibrosis through activation of autophagy.Front Pharmacol.2018;9:402.
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