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北京大学学报（医学版） ›› 2023, Vol. 55 ›› Issue (2): 283-291. doi: 10.19723/j.issn.1671-167X.2023.02.012

• 论著 • 上一篇    下一篇

青少年特发性脊柱侧凸椎旁肌的病理特征

郑丹枫1,李君禹2,3,李佳曦4,张英爽5,钟延丰1,于淼2,3,*()   

  1. 1. 北京大学基础医学院病理学系/北京大学第三医院病理科, 北京 100191
    2. 北京大学第三医院骨科, 北京 100191
    3. 北京大学第三医院脊柱疾病研究北京重点实验室, 北京 100191
    4. 北京大学基础医学院, 北京 100191
    5. 北京大学第三医院神经内科, 北京 100191
  • 收稿日期:2022-10-17 出版日期:2023-04-18 发布日期:2023-04-12
  • 通讯作者: 于淼 E-mail:miltonyu@126.com

Pathologic features of paraspinal muscle biopsies in patients with adolescent idiopathic scoliosis

Dan-feng ZHENG1,Jun-yu LI2,3,Jia-xi LI4,Ying-shuang ZHANG5,Yan-feng ZHONG1,Miao YU2,3,*()   

  1. 1. Department of Pathology, School of Basic Medical Sciences Peking University/Peking University Third Hospital, Beijing 100191, China
    2. Departmant of Orthopaedics, Peking University Third Hospital, Beijing 100191, China
    3. Beijing Key Laboratory of Spinal Disease Research, Peking University Third Hospital, Beijing 100191, China
    4. School of Basic Medical Sciences, Peking University, Beijing 100191, China
    5. Departmant of Neurology, Peking University Third Hospital, Beijing 100191, China
  • Received:2022-10-17 Online:2023-04-18 Published:2023-04-12
  • Contact: Miao YU E-mail:miltonyu@126.com

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摘要：

目的: 研究青少年特发性脊柱侧凸(adolescent idiopathic scoliosis, AIS)患者椎旁肌病理改变, 并进一步探讨抗肌萎缩蛋白(Dystrophin)在该病中的表达情况及其与病因的关系。方法: 收集2018年11月至2019年8月于北京大学第三医院诊断为AIS并接受后路侧弯矫形手术, 术中行凹侧顶椎椎旁肌活检患者18例。对肌肉活检组织进行规范化处理并切片进行常规苏木精-伊红(hematoxylin-eosin, HE)染色、多种组织化学染色以及抗肌萎缩蛋白各亚型、肌球蛋白、主要组织相容性复合体1(major histocompatibility complex 1, MHC-1)、CD4、CD8、CD20、CD68抗体的免疫组织化学染色及结果判读分析。此外, 根据Cobb角大小(≥55°或＜55°)和Nash-Moe分类将活检标本分为不同组别, 进行相应病理改变的组间差异统计学比较。结果: 18例患者中, 重度AIS组(Cobb角≥55°)8例, 轻度AIS组(Cobb角 < 55°)10例, 两组患者椎旁肌均出现不同程度萎缩、变性, Dystrophin-3的免疫组织化学染色均不同程度缺失且表达模式异常。两组活检肌纤维的Dystrophin-2的免疫组织化学染色切片中的表达模式存在显著差异, 重度AIS组的Dystrophin-2表达异常或缺失更显著。根据Nash-Moe分型分组, 患者椎旁肌的Dystrophin-2表达模式也有显著差异, 表现为侧凸程度越重, Dystrophin-2表达异常越显著。此外, 椎旁肌肉组织的肌肉和肌腱中存在CD4+细胞和CD8+细胞的浸润, 而CD20+细胞为阴性。全部患者椎旁肌均有部分肌纤维呈MHC-1肌膜阳性表达。结论: AIS患者椎旁肌活检的组织学具有相似的特征性改变, 抗肌萎缩蛋白的表达不同程度降低或缺失, 并且与脊柱侧凸程度有一定相关性, 提示抗肌萎缩蛋白功能障碍在脊柱侧凸的发生和发展中具有一定的意义。同时, AIS的炎症改变以T细胞浸润为主要表现, 炎症细胞浸润、MHC-1表达与抗肌萎缩蛋白异常表达之间似有一定的相关性。沿此结果进一步的研究可能为AIS的诊断和针对椎旁肌病变的治疗开辟新的思路。

关键词: 脊柱侧凸, 椎旁肌, 活组织检查, 青少年, 抗肌萎缩蛋白

Abstract:

Objective: To characterize the paraspinal muscles of adolescent idiopathic scoliosis (AIS) patients, and to further explore its etiology. Methods: Clinical records and paraspinal muscle biopsies at the apex vertebra region during posterior scoliosis correction surgery of 18 AIS were collected from November 2018 to August 2019. Following standardized processing of fresh muscle tissue biopsy, serial sections with conventional hematoxylin-eosin (HE) and histochemical and immunohistochemical (IHC) with antibody Dystrophin-1 (R-domain), Dystrophin-2 (C-terminal), Dystrophin-3 (N-terminal), Dystrophin-total, Myosin (fast), major histocompatibility complex 1 (MHC-1), CD4, CD8, CD20, and CD68 staining were obtained. Biopsy samples were grouped according to the subjects' median Cobb angle (Cobb angle ≥ 55° as severe AIS group and Cobb angle < 55° as mild AIS group) and Nash-Moe's classification respectively, and the corresponding pathological changes were compared between the groups statistically. Results: Among the 18 AIS patients, 8 were in the severe AIS group (Cobb angle ≥55°) and 10 in the mild AIS group (Cobb angle < 55°). Both severe and mild AIS groups presented various of atrophy and degeneration of paraspinal muscles, varying degrees and staining patterns of immune-expression of Dystrophin-3 loss, especially Dystrophin-2 loss in severe AIS group with significant differences, as well as among the Nash-Moe classification subgroups. Besides, infiltration of CD4+ and CD8+ cells in the paraspinal muscles and tendons was observed in all the patients while CD20+ cells were null. The expression of MHC-1 on myolemma was present in some muscle fibers. Conclusion: The histologic of paraspinal muscle biopsy in AIS had similar characteristic changes, the expression of Dystrophin protein was significantly reduced and correlated with the severity of scoliosis, suggesting that Dystrophin protein dysfunctions might contribute to the development of scoliosis. Meanwhile, the inflammatory changes of AIS were mainly manifested by T cell infiltration, and there seemed to be a certain correlation between inflammatory cell infiltration, MHC-1 expression and abnormal expression of Dystrophin. Further research along the lines of this result may open up new ideas for the diagnosis of scoliosis and the treatment of paraspinal myopathy.

Key words: Scoliosis, Paraspinal muscles, Biopsy, Adolescent, Dystrophin protein

中图分类号: 

  • R682.3

表1

AIS患者的临床特征"

Patient no. Age/years Age of onset/years Nash-Moe classification Cobb curve angle of thoracic vertebra/(°)
1 12 12 Ⅰ 51.4
2 16 16 Ⅱ 58.5
3 18 18 Ⅲ 73.6
4 22 22 Ⅰ 25.8
5 15 15 Ⅰ 28.3
6 16 16 Ⅰ 29.9
7 20 20 Ⅱ 76.5
8 27 27 Ⅱ 62.5
9 16 16 Ⅰ 33.3
10 16 16 Ⅱ 55.1
11 15 15 Ⅰ 56.8
12 13 13 Ⅱ 57.5
13 15 15 Ⅲ 65.6
14 12 12 Ⅰ 58.1
15 15 15 Ⅰ 44.8
16 14 14 Ⅱ 24.7
17 16 16 Ⅱ 45.4
18 12 12 Ⅲ 70.9

图1

AIS患者椎旁肌活检切片"

表2

不同Cobb角分组AIS患者肌肉活检病理学特点(n=18)"

Pathological feature or staining pattern Severe scoliosis (Cobb≥55°, n=10) Mild scoliosis (Cobb < 55°, n=8) P
Atrophy degree 0.706
    Mild-moderate 0 1 (12.5)
    Moderate-severe 9 (90) 7 (87.5)
    Severe 1 (10) 0
Atrophy pattern 0.275
    Big group 1 (10) 3 (37.5)
    Small group 9 (90) 5 (62.5)
Degeneration of myofibers >0.999
    None 7 (70) 6 (75.0)
    Present 3 (30) 2 (25.0)
Edema 0.846
    None 4 (40) 4 (50.0)
    Few 4 (40) 2 (25.0)
    Most 2 (20) 2 (25.0)
Whorled fibers 0.321
    None 8 (80) 4 (50.0)
    Present 2 (20) 4 (50.0)
Hypertrophic fibers 0.183
    None 0 2 (25.0)
    Present 10 (100) 6 (75.0)
Internal nuclei >0.999
    None 1 (10) 1 (12.5)
    Present 9 (90) 7 (87.5)
Moth-eaten in NADH-TR 0.153
    None 3 (30) 6 (75.0)
    Present 7 (70) 2 (25.0)
Myosin staining pattern 0.427
    None 0 1 (12.5)
    Several 2 (20) 3 (37.5)
    Small part 8 (80) 4 (50.0)
Dystrophin-1 staining pattern 0.151
    Dizzy lineation 3 (30) 5 (62.5)
    Light-colored lineation 4 (40) 0
    Discontinuous lineation 3 (30) 3 (37.5)
Dystrophin-2 staining pattern 0.047
    Dizzy lineation 3 (30) 7 (87.5)
    Light-colored lineation 3 (30) 0
    Discontinuous lineation 4 (40) 1 (12.5)
Dystrophin-3 staining pattern 0.798
    Dizzy lineation 0 1 (12.5)
    Light-colored lineation 5 (50) 3 (37.5)
    Discontinuous lineation 5 (50) 4 (50.0)
Dystrophin-total staining pattern 0.069
    Dizzy lineation 3 (30) 7 (87.5)
    Light-colored lineation 4 (40) 0
    Discontinuous lineation 3 (30) 1 (12.5)

图2

AIS患者椎旁肌肉活检Dystrophin-2和Dystrophin-total的免疫组织化学染色"

图3

AIS患者椎旁肌活检中Dystrophin-1(杆状结构域表位)和Dystrophin-3(N末端表位)免疫组织化学染色"

表3

不同Nash-Moe分型AIS患者肌肉活检病理学特点(n=18)"

Pathological features or staining pattern Nash-Moe type Ⅰ (n=8) Nash-Moe type Ⅱ (n=7) Nash-Moe type Ⅲ (n=3) P
Atrophy degree 0.314
    Mild-moderate 1 (12.5) 0 0
    Moderate-severe 7 (87.5) 7 (100.00) 2 (66.67)
    Severe 0 0 1(33.33)
Atrophy pattern >0.999
    Big group 2 (25.0) 2 (28.57) 0
    Small group 6 (75.0) 5 (71.43) 3 (100.00)
Degeneration of myofibers >0.999
    None 6 (75.0) 5 (71.43) 2 (66.67)
    Present 2 (25.0) 2 (28.57) 1 (33.33)
Edema 0.580
    None 2 (25.0) 4 (57.14) 2 (66.67)
    Few 4 (50.0) 2 (28.57) 0
    Most 2 (25.0) 1 (14.29) 1 (33.33)
Whorled fibers 0.451
    None 4 (50.0) 5 (71.43) 3 (100.00)
    Present 4 (50.0) 2 (28.57) 0
Hypertrophic fibers >0.999
    None 1 (12.5) 1 (14.29) 0
    Present 7 (87.5) 6 (85.71) 3 (100.00)
Internal nuclei 0.451
    None 1 (12.5) 0 1 (33.33)
    Present 7 (87.5) 7 (100.00) 2 (66.67)
Moth-eaten in NADH-TR 0.698
    None 5 (62.5) 3 (42.86) 1 (33.33)
    Present 3 (37.5) 4 (57.14) 2 (66.67)
Myosin staining pattern 0.762
    None 1 (12.5) 0 0
    Several 1 (12.5) 3 (42.86) 1 (33.33)
    Small part 6 (75.0) 4 (57.14) 2 (66.67)
Dystrophin-1 staining pattern 0.075
    Dizzy lineation 5 (62.5) 1 (14.29) 2 (66.67)
    Light-colored lineation 0 4 (57.14) 0
    Discontinuous lineation 3 (37.5) 2 (28.57) 1 (33.33)
Dystrophin-2 staining pattern 0.043
    Dizzy lineation 7 (87.5) 3 (42.86) 0
    Light-colored lineation 0 2 (28.57) 1 (33.33)
    Discontinuous lineation 1 (12.5) 2 (28.57) 2 (66.67)
Dystrophin-3 staining pattern >0.999
    Dizzy lineation 1 (12.5) 0 0
    Light-colored lineation 3 (37.5) 4 (57.14) 1 (33.33)
    Discontinuous lineation 4 (50.0) 3 (42.86) 2 (66.67)
Dystrophin-total staining pattern 0.441
    Dizzy lineation 5 (62.5) 2 (28.57) 3 (100.00)
    Light-colored lineation 1 (12.5) 3 (42.86) 0
    Discontinuous lineation 2 (25.0) 2 (28.57) 0

图4

AIS患者椎旁肌活检中炎症浸润情况"

图5

CD68+细胞浸润于肌腱及肌束间质小血管周围(CD68 ×40)"

1 Cheng JC , Castelein RM , Chu WC , et al. Adolescent idiopathic scoliosis[J]. Nat Rev Dis Primers, 2015, 1, 15030.
doi: 10.1038/nrdp.2015.30
2 Weinstein SL . The natural history of adolescent idiopathic scoliosis[J]. J Pediatr Orthop, 2019, 39 (6): S44- S46.
3 Spencer GS , Eccles MJ . Spinal muscle in scoliosis: Part 2. The proportion and size of type 1 and type 2 skeletal muscle fibres measured using a computer-controlled microscope[J]. J Neurol Sci, 1976, 30 (1): 143- 154.
doi: 10.1016/0022-510X(76)90262-8
4 Fidler MW , Jowett RL . Muscle imbalance in the aetiology of sco-liosis[J]. J Bone Joint Surg B, 1976, 58 (2): 200- 201.
5 Khosla S , Tredwell SJ , Day B , et al. An ultrastructural study of multifidus muscle in progressive idiopathic scoliosis. Changes resulting from a sarcolemmal defect at the myotendinous junction[J]. J Neurol Sci, 1980, 46 (1): 13- 31.
doi: 10.1016/0022-510X(80)90040-4
6 Tidball JG . Myotendinous junction: Morphological changes and mechanical failure associated with muscle cell atrophy[J]. Exp Mol Pathol, 1984, 40 (1): 1- 12.
doi: 10.1016/0014-4800(84)90060-1
7 Wajchenberg M , Martins DE , Luciano RP , et al. Histochemical analysis of paraspinal rotator muscles from patients with adolescent idiopathic scoliosis: A cross-sectional study[J]. Medicine (Baltimore), 2015, 94 (8): e598.
doi: 10.1097/MD.0000000000000598
8 Luciano Rde P , Puertas EB , Martins DE , et al. Adolescent idiopathic scoliosis without limb weakness: A differential diagnosis of core myopathy?[J]. BMC Musculoskelet Disord, 2015, 16, 179.
doi: 10.1186/s12891-015-0629-8
9 Zoabli G , Mathieu PA , Aubin CE . Magnetic resonance imaging of the erector spinae muscles in Duchenne muscular dystrophy: Implication for scoliotic deformities[J]. Scoliosis, 2008, 3, 21.
doi: 10.1186/1748-7161-3-21
10 Nash CL Jr , Moe JH . A study of vertebral rotation[J]. J Bone Joint Surg Am, 1969, 51 (2): 223- 229.
doi: 10.2106/00004623-196951020-00002
11 Dubowitz V , Sewry CA , Oldfors A , et al. Muscle biopsy: A practical approach[M]. 4th ed. Oxford, England: Saunders Else-vier, 2013.
12 Altaf F , Gibson A , Dannawi Z , et al. Adolescent idiopathic sco-liosis[J]. BMJ, 2013, 346, f2508.
doi: 10.1136/bmj.f2508
13 Brzoska E , Kalkowski L , Kowalski K , et al. Muscular contribution to adolescent idiopathic scoliosis from the perspective of stem cell-based regenerative medicine[J]. Stem Cells Dev, 2019, 28 (16): 1059- 1077.
doi: 10.1089/scd.2019.0073
14 Veldhuizen AG , Wever DJ , Webb PJ . The aetiology of idiopathic scoliosis: Biomechanical and neuromuscular factors[J]. Eur Spine J, 2000, 9 (3): 178- 184.
doi: 10.1007/s005860000142
15 Meier MP , Klein MP , Krebs D , et al. Fiber transformations in multifidus muscle of young patients with idiopathic scoliosis[J]. Spine (Phila Pa 1976), 1997, 22 (20): 2357- 2364.
doi: 10.1097/00007632-199710150-00008
16 Bylund P , Jansson E , Dahlberg E , et al. Muscle fiber types in thoracic erector spinae muscles[J]. Clin Orthop Relat Res, 1987, (214): 222- 228.
17 Mannion AF , Meier M , Grob D , et al. Paraspinal muscle fibre type alterations associated with scoliosis: an old problem revisited with new evidence[J]. Eur Spine J, 1998, 7 (4): 289- 293.
doi: 10.1007/s005860050077
18 Hoffman EP , Brown RH Jr , Kunkel LM . Dystrophin: The protein product of the Duchenne muscular dystrophy locus[J]. Cell, 1987, 51 (6): 919- 928.
doi: 10.1016/0092-8674(87)90579-4
19 Ervasti JM , Campbell KP . Membrane organization of the dystrophin-glycoprotein complex[J]. Cell, 1991, 66 (6): 1121- 1231.
doi: 10.1016/0092-8674(91)90035-W
20 Houang EM , Sham YY , Bates FS , et al. Muscle membrane integrity in Duchenne muscular dystrophy: Recent advances in copolymer-based muscle membrane stabilizers[J]. Skelet Muscle, 2018, 8 (1): 31.
doi: 10.1186/s13395-018-0177-7
21 Yiu EM , Kornberg AJ . Duchenne muscular dystrophy[J]. J Paediatr Child Health, 2015, 51 (8): 759- 764.
doi: 10.1111/jpc.12868
22 Wilson K , Faelan C , Patterson-Kane JC , et al. Duchenne and Becker muscular dystrophies: A review of animal models, clinical end points, and biomarker quantification[J]. Toxicol Pathol, 2017, 45 (7): 961- 976.
doi: 10.1177/0192623317734823
23 Goebel HH , Sewry CA , Weller RO . Muscle disease: Pathology and genetics[M]. 2nd ed. New Jersey, USA: Wiley-Blackwell, 2013: 95- 100.
24 Gherardi RK . Pathogenic aspects of dermatomyositis, polymyositis and overlap myositis[J]. Presse Med, 2011, 40 (4 Pt 2): e209- e218.
25 Samaan MC , Missiuna P , Peterson D , et al. Understanding the role of the immune system in adolescent idiopathic scoliosis: Immunometabolic CONnections to Scoliosis (ICONS) study protocol[J]. BMJ Open, 2016, 6 (7): e011812.
doi: 10.1136/bmjopen-2016-011812
26 Rudrapatna S , Peterson D , Missiuna P , et al. Understanding muscle-immune interactions in adolescent idiopathic scoliosis: A feasibility study[J]. Pilot Feasibility Stud, 2017, 3, 50.
doi: 10.1186/s40814-017-0193-0
27 Van Gennip JLM , Boswell CW , Ciruna B . Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis[J]. Sci Adv, 2018, 4 (12): eaav1781.
doi: 10.1126/sciadv.aav1781
28 Dalkilic I , Kunkel LM . Muscular dystrophies: Genes to pathoge-nesis[J]. Curr Opin Genet Dev, 2003, 13 (3): 231- 238.
doi: 10.1016/S0959-437X(03)00048-0
29 Fiorillo AA , Heier CR , Novak JS , et al. TNF-α-induced micro-RNAs control dystrophin expression in Becker muscular dystrophy[J]. Cell Rep, 2015, 12 (10): 1678- 1690.
doi: 10.1016/j.celrep.2015.07.066
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