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研究生：	黃國淵 Huang, Kuo-Yuan
論文名稱：	IL-19及IL-20和椎間盤受傷的關係 The Association of IL-19 and IL-20 with Intervertebral Disc Injury
指導教授：	張明熙 Chang, Ming-Shi 林瑞模 Lin, Ruey-Mo
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	95
中文關鍵詞：	IL-19 、IL-20 、BMP-2 、椎間盤突出、退化性腰椎滑脫、發炎、退化、中軸加壓載重核磁共振影像
外文關鍵詞：	IL-19, IL-20, BMP-2, intervertebral disc herniation, degenerative lumbar spondylolisthesis, inflammation, degeneration, axially-loaded MRI
相關次數：	點閱：184 下載：2
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研究一、IL-19, IL-20在椎間盤突出及腰椎退化性滑脫所扮演的角色
椎間盤突出後引發的發炎反應被認為是引起下背痛和坐骨神經痛的主要原因。新的細胞素IL-19和IL-20，屬於 IL-10家族，涉入各種不同的發炎性疾病。然而，目前並無研究顯示IL-19和 IL-20如何影響椎間盤傷害後的發炎反應，癒合過程和脊柱的退化。我們的研究發現，IL-20和其受體表現在人類的椎間盤突出組織及培養出的椎間盤細胞中。椎間盤細胞上有 IL-20受體而且可以被IL-20所作用。在體外實驗中，IL-1β可誘發椎間盤細胞表現IL-20，而且IL-20聯合IL-1β可以誘發椎間盤細胞表現各種不同細胞素、趨化因子、血管新生因子及基質金屬蛋白酵素（matrix metalloproteinases；MMPs）。因此，IL-20連同IL-1β在椎間盤受傷後會造成發炎反應的增強，IL-20可能與椎間盤突出的病理機轉有關。退化性的腰椎滑脫是起源於椎間盤受傷，通常發生在 L4/L5節，因脊椎面關節鎖定機制失效後發生。造成退化性的腰椎滑脫症狀的因子很多，包括脊柱的不穩定、神經壓迫的程度和發炎反應等。然而在臨床的研究中，退化性的腰椎滑脫的症狀並不全然與患者的核磁共振影像上脊柱退化及神經壓迫的嚴重度有相關，因此發炎反應可能在退化性腰椎滑脫的致病機轉扮演一個重要的角色；儘管如此，對於IL-19 和 IL-20是否表現於退化性腰椎滑脫的組織及其病理生理學功能的研究至今還仍是未知。因此，我們探討IL-19及IL-20是否與退化性的腰椎滑脫的病理機轉有關。我們發現從退化性的腰椎滑脫患者手術中取得的檢體中，IL-19、IL-20、IL-20R1、IL-20R2、TNF-α、IL-1β和MCP-1會共同表現在退化的椎間盤、小面關節和黃韌帶組織的組織樣本中。IL-19及IL-20的表現與發炎性細胞素TNF-α和IL-1β的表現及趨化因子MCP-1和IL-8的表現有關。在體外實驗，IL-19 和 IL-20在CoCl2 模擬的缺氧情況之下，對退化性的腰椎滑脫的病患的退化椎間盤組織培養所得的人類椎間盤細胞，會誘發促炎細胞素、趨化因子的表現及血管新生的反應。因此，IL-19和IL-20在退化性的腰椎滑脫的病患的椎間盤、小面關節和黃韌帶組織上，可能會促進發炎反應的過程，因此IL-19和IL-20可能參與退化性的腰椎滑脫的致病機轉。

研究二、椎間盤內加入RhBMP-2對受傷之椎間盤生體內的影響
RhBMP-2，是一個很強效的骨骼誘導及軟骨誘導因子，已經為美國食品藥物管理局核准可以使用於人類脊柱的前融合手術，也可以修復受傷的軟骨。我們發現BMP-2表現在人類椎間盤突出的組織上。然而，rhBMP-2對受傷的椎間盤組織之體內反應研究的很少。我們的研究發現在兔子椎間盤受傷之動物模式中，受傷的椎間盤區域會出現各種不同程度的退化；而接受rhBMP-2處理的組別出現較嚴重的退化如骨刺生成。病理組織的研究發現椎間盤受傷之後，rhBMP-2會促進血管新生和發炎反應；這兩個反應是骨骼融合過程的最初兩個階段。因此，rhBMP-2 可能與椎間盤受傷後的傷害反應，癒合過程及後續之脊柱退化有關。

研究三、影響退化性腰椎滑脫病患身體失能及生理功能的因子
中軸加壓載重之核磁共振影像檢查是對於偵測脊椎疾病的動態或隱藏的變化很有用的診斷工具，它可以模擬直立時腰椎所承受的重力及中軸加壓狀態。除了IL-19和IL-20在退化性腰椎滑脫的發炎反應所扮演的角色外，我們希望藉由中軸加壓載重之核磁共振檢查，進一步去分析與退化性腰椎滑脫病患身體失能及生理功能有關的重要生物力學因子及探討中軸加壓載重對脊柱及脊椎管腔形態學上的影響。所有病患接受未加壓及中軸加壓的核磁共振檢查。我們量測核磁共振影像的預測變數包括：L4-5受壓前後椎間盤高度變化、椎體間位移變化、椎間盤角度變化、硬脊膜橫斷面面積的變化及L1-5加壓前及加壓後腰椎脊柱前凸的曲線角。我們發現：L4-5 退化性腰椎滑脫的患者，接受中軸加壓載重核磁共振影像的檢查，發現L4-5椎間盤角度的不穩定和身體的失能及生理功能有相關；而加壓後的腰椎脊柱前凸的曲線角也和L4-5 退化性腰椎滑脫患者的生理功能具有好的相關性。L4-5的椎間盤角度變化可以是預測L4-5 退化性腰椎滑脫的患者失能的良好指標。
總結來說，我們發現在椎間盤受傷之後，IL-19、IL-20和BMP-2是調控發炎、癒合過程和脊柱的退化的關鍵因素；我們也發現椎間盤角度的不穩定與退化性腰椎滑脫的患者身體的失能及生理功能有相關。

Study 1. The Roles of IL-19, IL-20 on Intervertebral Disc Herniation and Degenerative Lumbar Spondylolisthesis
The inflammatory reaction after intervertebral disc herniation (HIVD) was considered as the major cause of low back pain and sciatica. IL-19 and IL-20, members of IL-10 family, are involved in various inflammatory diseases. However, little is known on how IL-19 and IL-20 affect the inflammation, healing process, and degeneration of spine after intervertebral disc injury. We reported the expression of IL-20 and its receptors in the primarily cultured disc cells as well as in human herniated intervertebral disc (HIVD) tissues. Disc cells express IL-20 receptors and are targeted by IL-20. In vitro, IL-1β induced the expression of IL-20, and IL-20 combined with IL-1β induced the expression of various cytokines, chemokines, angiogenetic factors, and matrix metalloproteinases (MMPs) in human disc cells. Therefore, IL-20 together with IL-1β enhances the inflammatory process after disc injury, and IL-20 may contribute to the pathogenesis of HIVD. Degenerative lumbar spondylolisthesis (DLS) results from disc injury, which usually occurs at the L4/L5 level after the facet-joint locking mechanism fails. The etiology of DLS is multifactorial, and includes spinal instability, neurological compromise and inflammation. In clinical practice, symptoms are not well correlated with the severity of degeneration and neural compression on MRIs of patients with DLS. Inflammation may play an important role in the pathogenesis of DLS; however, expression of IL-19 and IL-20 and their pathophysiological function in DLS has not been explored. Thus, we explored if IL-19 and IL-20 were associated with DLS. We found that IL-19, IL-20, IL-20R1 and IL-20R2, TNF-α, IL-1β and MCP-1 were co-localized in tissue samples of degenerated discs, facet joints, and ligamentum flavum retrieved from patients with DLS. The expression of IL-19 and IL-20 is associated with the expression of the inflammatory cytokines, TNF-α and IL-1β and the chemokines, MCP-1 and IL-8. In vitro, IL-19 and IL-20 induced the expression of proinflammatory cytokines, chemokine, and angiogenesis under CoCl2-mimicked hypoxia condition in the primarily cultured human disc cells, which isolated from degenerated disc tissues of patients with DLS. Therefore, IL-19 and IL-20 may contribute to the inflammatory process in discs, facet joints, and the ligamentum flavum in patients with DLS；IL-19 and IL-20 may be involved in the pathogenesis of DLS.

Study 2. The in vivo Biological Effects of Intra-discal RhBMP-2 on the Injured Intervertebral Disc
RhBMP-2, a potent osteoinductive and chondroinductive factor, has been approved for use in human anterior spinal fusion and can promote cartilage repair. We found that BMP-2 can be expressed in the human herniated disc specimen. However, the in vivo response of intra-discal rhBMP-2 on the injured IVDs is not clear. We found that various degrees of degenerative change around the injured disc space in our rabbit disc injury model. More severe spondylosis, such as spur formation, was found in the groups treated with rhBMP-2. The pathological findings revealed that rhBMP-2 promotes angiogenesis and inflammation after disc injury; which are known as the first two stages of bone incorporation for fusion. Therefore, rhBMP-2 might contribute to the injury response, healing process and subsequent degeneration after disc injury.

Study 3. Factors Affecting Disability and Physical Function in Degenerative Lumbar Spondylolisthesis
Axially-loaded magnetic resonance image (MRI) is a useful diagnostic tool, enabling detection of dynamic or occult changes of spinal disorders by simulating the upright position under normal gravity and mimicking the condition of axial compression in the lumbar spine. Except the roles of IL-19 and IL-20 in the inflammation process of degenerative lumbar spondylolisthesis (DLS), we aimed to further analyze the critical biomechanical factors responsible for the disability and physical function of patients with DLS using axially-loaded MRI, and to investigate the effect of axial loading on the morphology of the spine and the spinal canal. All patients underwent unloaded and axially-loaded MRI. We measured the predictors on MRI, including the differences of disc height (DH), sagittal translation (ST), segmental angulation (SA), and dural sac cross-sectional area (DCSA) at L4-5 between the unloaded and axially-loaded condition, as well as pre-load and post-load lumbar lordotic angles (LLA) at L1-5. We discovered that angular instability is correlated with physical disability and physical function for patients with L4-5 DLS in an axially-loaded magnetic resonance image (MRI); the post-load lumbar lordotic curve angle is also well correlated with physical function for patients with L4-5 DLS. Segmental angulation of L4-5 can be a good indicator of disability in patients with L4-5 DLS.
In conclusion, we discovered that IL-19, IL-20, and BMP-2 may be the key factors to modulate inflammation, healing process and degeneration of spine after intervertebral disc injury. Besides, we also discovered that angular instability of intervertebral disc is correlated with physical disability and physical function for patients with L4-5 DLS.

中文摘要	                                                      I
Abstract	                                      IV
誌謝	                                                    VII
Table of Contents	                             VIII
List of Tables	                                      XII
List of Figures	                                      XIV
Abbreviation List	                              XVI

Study 1. The roles of IL-19, IL-20 on intervertebral disc herniation and degenerative lumbar spondylolisthesis	1
I. Background	                                        1
HIVD and low back pain	                                1
HIVD and inflammation	                                1
Degenerative Lumbar Spondylolisthesis (DLS)	        2
Degenerative lumbar spondylolisthesis (DLS) and inflammation	                                                3
IL-19 and IL-20, members of IL-10 family	        3
II. Rationale	                                        5
III. Specific aims	                                7
To study the role of IL-20 in human intervertebral disc herniation	                                        7
To study the roles of IL-19 and IL-20 in the pathogenesis of degenerative lumbar spondylolisthesis (DLS)	        7
IV. Materials and Methods	                        8
Reagents, antibody and protein preparation in study of IL-20 with HIVD	                                        8
Reagents and antibody in study of IL-19, IL-20 with DLS	8
Patients	                                        8
HIVD Patients.	                                        8
DLS Patients.	                                        8
Immunohistochemical staining of human herniated intervertebral disc tissues	                        10
Primary culture of human intervertebral disc cells in HIVD patients	                                        10
Immunohistochemical staining of human disc cells	10
Detection of gene expression in disc cells treated with IL-20 alone and in combination with IL-1β and IL-1β alone, using reverse transcription– polymerase chain reaction (RT-PCR)	                                                11
ELISA analysis of cytokines expression	                11
Immunohistochemical staining of disc, facet joint, and ligamentum flavum in the DLS patients                   12
Primary culture of human intervertebral disc cells in DLS patients	                                        12
Detection of the effect of IL-19 or IL-20 on the gene expressions of proinflammatory cytokines (TNF-α, IL-1β,and IL-6), chemokines (IL-8, and MCP-1), and angiogenetic factor (VEGF) in disc cells under hypoxia condition using real-time quantitative PCR	                        12
Statistical Analysis	                                13
V. Results	                                        14
The role of IL-20 in human intervertebral disc herniation	                                                14
The expression of IL-20 and its receptors in human IVD tissue	                                                14
The expression of IL-20 and its receptors in primarily cultured disc cells	                                14
IL-20 combined with IL-1β induced multiple gene expression in primary disc cells	                                15
The roles of IL-19 and IL-20 in degenerative lumbar spondylolisthesis	                                16
Immunohistochemical staining	                        16
Expression and localization of TNF-α, IL-1β and MCP-1 positive cells	                                        17
Correlative Analyses	                                18
Up-regulation of proinflammatory cytokines and chemokine in disc cells by IL-19 and IL-20	                        18
VI. Discussion	                                        20
The role of IL-20 in human intervertebral disc herniation	                                                20
The roles of IL-19 and IL-20 in degenerative lumbar spondylolisthesis	                                21
VII. Conclusion	                                        24

Study 2. The in vivo biological effects of intra-discal rhBMP-2 on the injured intervertebral disc	        25
I. Background	                                        25
II. Rationale	                                        27
III. Specific aims	                                28
To study the role of BMP-2 in the injured intervertebral disc	                                                28
IV. Materials and Methods	                        29
Animal experimental procedures	                        29
Radiographic Analysis	                                30
Histopathologic Analysis	                        30
Fusion Assessment	                                31
Statistical Analysis	                                31
V. Results	                                        32
Gross Findings and Fusion Status	                32
Radiographic Findings	                                32
Histopathologic Findings	                        32
VI. Discussion	                                        34
VII. Conclusion	                                        38

Study 3. Factors affecting disability and physical function in degenerative lumbar spondylolisthesis	        39
I. Background	                                        39
II. Rationale	                                        41
III. Specific aims	                                42
To study factors affecting physical disability and physical function in degenerative lumbar spondylolisthesis under the axially-loaded MRI	                                42
IV. Materials and Methods	                        43
DLS Patients	                                        43
Axially-loaded magnetic resonance imaging (MRI)	        43
Spinal parameters measured from axially-loaded MRI	44
Statistical analysis	                                45
V. Results	                                        46
VI. Discussion	                                        48
VII. Conclusion	                                        52
Tables	                                                53
Figures and figure legends	                        66
References	                                        79
Publication	                                        95


                                    

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