背景：顳顎關節障礙症(Temporomandibular joint disorder, TMD)為常見之牙科疾病，通常會因疼痛而間接影響關節運動，導致病患生活品質降低。當發炎時期，許多細胞素或蛋白水解酶被誘導出，易造成關節內部硬組織或軟組織受損，進而影響正常功能。由於顳顎關節(Temporomandibular joint, TMJ)軟骨結構主要由纖維軟骨構成，其中具有穩定蛋白聚醣與玻尿酸之間鍵結的連接蛋白(Link protein)，會因基質金屬蛋白酶(Matrix metalloproteinases, MMPs)而降解出一段由16 個胺基酸組成的連接蛋白N 端胜肽(Link protein N terminal peptide, Link N)。在同屬於纖維軟骨組織之椎間盤疾病研究顯示，此胜肽片段具有調節發炎和修復組織的功效，但目前顳顎關節炎之動物模式尚未使用連接蛋白N 端胜肽進行治療;此外若此胜肽未來可利用於臨床之治療，勢必先了解病患關節內在不同病變時期之變化，透過核磁共振(Magnetic Resonance Imaging, MRI)，以及關節沖洗出之物質來輔助醫師診斷分析。因此本研究之目的：(1)探討連接蛋白N 端胜肽於細胞及大鼠顳顎關節炎動物模式之效益。(2)利用影像學及關節液來評估與分析顳顎關節障礙症。
材料與方法：(1)人類間質幹細胞(Human mesenchymal stem cells, hMSCs)與1ng/mL介白素1β (Interleukin-1β, IL-1β) 、1μg/mL 連接蛋白N 端胜肽(DHLSDNYTLDHDRAIH)共同培養，分別於24 小時及96 小時刺激後收集細胞上清液，以多功能的螢光生物分子多重分析系統分析細胞素的表現，此外收集細胞以觀察24 小時基因的表現。注射50μL 阿爾襄藍染劑(Alcian blue)於大鼠兩側之顳顎關節上關節腔內，以確認注射技術之有效性。分別於第0 天及第7 天注射弗氏佐劑(Complete Freund's Adjuvant, CFA)以誘導大鼠關節發炎後，於第14 天給予0.01mg/μL 連接蛋白N 端胜肽治療，第35 天犧牲後，使用蘇木素-伊紅染色(Hematoxylin and Eosin stain, HE stain)觀察組織型態。(2)27 位顳顎關節障礙症病患以數字疼痛量表(Numeric rating scale, NRS)來評估疼痛程度，並於MRI 拍攝後，依照Wilkes、關節髁頭形變、關節積液之等級分類，再收集病患沖洗出之關節液，使用多功能螢光生物分子多重分析系統來分析關節液內細胞素的表現。
結果：(1)在單獨IL-1β 刺激細胞發炎的環境下，發炎分子IL-6、丙型干擾素誘導蛋白(Interferon gamma-inducible protein, IP-10)、調節活化正常T 細胞表達與分泌趨化因子(Regulated on activation, normal T cell expressed and secreted, RANTES)明顯上升，但在同時有連接蛋白N 端胜肽的環境下，三個分子表現卻明顯下降。相反的，抗發炎分子IL-4、IL-10，以及軟骨分化相關分子如轉化生長因子β1-3 (Transforming growth factor β1-3, TGFβ1-3)和erb-b2 receptor tyrosine kinase 3 (ERBB3)、Nodal homolog (NODAL)基因在共同刺激組與IL-1β 組相比，顯著上升。在CFA 誘導顳顎關節發炎的大鼠模式中，原來變薄的髁頭軟骨(Condylar cartilage, CC)層，在給予連接蛋白N 端胜肽後，有恢復的表現。(2)將27 位顳顎關節障礙症病患之影像進行分析，發現Wilkes 分類與關節髁頭型變有相關性，但與關節積液無相關性。此外關節積液與NRS 有正相關，但與Wilkes 和關節髁頭型變無相關性。相較於關節髁頭型變，關節積液與較多發炎因子IL-8、游離性的介白素6 受器(Soluble IL-6 receptor,
sIL-6R)和抗發炎因子游離性的腫瘤壞死因子受器I/II (Soluble TNF receptor I/II,sTNF-RI/II)有相關性。
結論：在本研究之條件下，在細胞實驗中，連接蛋白N 端胜肽可扮演調節者的角色，幫忙緩解發炎的環境，並增加軟骨相關之分子表現。另外在動物實驗，在給予大鼠顳顎關節炎之治療後，從組織切片可以清楚觀察到關節髁頭的分層有恢復的現象，因此可以初步推測連接蛋白N 端胜肽，具有治療發炎關節的潛力。透過臨床上常見之MRI 影像學分類，關節積液的有無，與較多細胞素表現有相關性，因此可作為顳顎關節障礙症評估的有效指標之一。期望藉由本研究能夠證明出連接蛋白N 端胜肽對於顳顎關節炎之治療潛力，並且透過臨床上更多元的影像學的分類方法，期望能提供牙醫師們在臨床上有更客觀之評估方式。

Background: Temporomandibular joint disorders (TMDs) is a common joint disorder which affecting masticatory actions; it includes joint clicking, joint or muscle pain, and limitations of jaw movement. Under inflammatory conditions, some of cytokines and proteolytic enzymes are induced which may destroy the hard or soft tissue in joint, thereby affecting its function. Due to the cartilage of temporomandibular joint (TMJ) consists of
fibrocartilage, there is a small peptide named Link N which is released from the link protein by matrix metalloproteinase (MMPs). As the same structure of intervertebral disc (IVD), Link N possesses ability to regulate inflammation and joint repair. However, manuscripts are lacking regarding the application of this peptide for TMJ arthritis treatment. If Link N can be used in clinical, we need to realize the change in different pathologic stages. Through the magnetic resonance imaging (MRI) and the cytokine expression in human synovial fluid which may assist clinician for joint diagnosis. Therefore, the aim of this study are: (1) To evaluate the potential of Link N in human mesenchymal stem cells (hMSCs) and in rat TMJ arthritis animal model. (2) To validate the correlation of different MRI grades with cytokine levels of synovial fluid in TMDs patients.
Materials and methods: (1) Cytokines and genes in hMSCs treated with 1μg/mL Link N, 1ng/mL IL-1β, and co-stimulation were undertaken using Luminex multiplex assays and PCR array, respectively. 50μL alcian blue was injected into rat superior TMJ space to confirm the precision of injection skill. At day 0 and day 7, CFA was injected to induce joint inflammation. 0.01mg/μL Link N treatment displayed at day 14. After 35 days following, the tissue morphology was determined by HE stain. (2) 27 patients, who routinely received numeric rating scale (NRS) and MRI assessment before TMJ arthrocentesis, were enrolled. Joint synovial fluid, collected through arthrocentesis were examined for cytokine expression by using a Luminex multiplex assay.
Results: (1) Increased levels of IL-6, IP-10 and RANTES were detected in response to IL-1β treatment, but significantly decreased in the co-stimulation group. In contrast, IL-4, IL-10, TGFβ1-3, ERBB3 and NODAL, were increased significantly in the costimulation group compared to the IL-1β group. Histologic analysis showed significant recovery for rat CC layer in the Link N group when compared to the CFA induced arthritis group. (2) The Wilkes classification was strongly correlated with osseous change scores, but not with joint effusion scores. Joint effusion scores significantly correlated with NRS scores, but not with the Wilkes classification and osseous change scores. Compared with osseous change scores, joint effusion scores had a higher correlation with the levels of inflammatory cytokines (IL-8, sIL-6R) and with anti-inflammatory cytokines (sTNFRI/II).
Discussion: In vivo study, Link N could reduce inflammatory condition and stimulate chondrocyte related factors expression. After injecting Link N in rat TMJ arthritis model, the joint thickness was recovery can be found. Based on these evidence, it could presume that Link N has a potential for arthritis treatment. Through MRI classification, joint effusion scoring showed high correlation with cytokines. It can be a reliable and valid indicator for pathological assessment of TMDs. Results of this study could prove the repair potential of Link N in TMJ arthritis and provide dentist objective evaluation methods through adjective image classification.

中文摘要.................................................i
英文摘要.............................................. iii
目錄 .................................................. v
第一章 緒論 ............................................ 1
第一節 顳顎關節之結構 ................................... 1
第二節 顳顎關節炎 ....................................... 2
第三節 顳顎關節炎之動物模式 .............................. 4
第四節 連接蛋白N 端胜肽之功能 ............................ 7
第五節 連接蛋白N 端胜肽之應用 ............................ 8
第六節 顳顎關節障礙症之影像評估 ......................... 10
第七節 人類顳顎關節液 .................................. 12
第二章 研究設計與目的 .................................. 14
目的一、探討連接蛋白N 端胜肽於細胞及動物實驗之效益 ........ 14
目的二、利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 15
第三章 研究材料與方法 .................................. 16
第一節 連接蛋白N 端胜肽效益之探討 ....................... 16
3.1.1 連接蛋白N 端胜肽製備 ............................. 16
3.1.2 人類間質幹細胞(Human mesenchymal stem cells, hMSCs)收集及培養 .............................................. 16
3.1.3 細胞素之定量 .................................... 16
3.1.4 核糖核酸(RNA)萃取及聚合酶連鎖反應(Polymerase chain reaction, PCR) ....................................... 17
3.1.5 CFA 誘導顳顎關節炎之大鼠動物模式 .................. 17
3.1.6 組織蘇木素-伊紅(Hematoxylin and Eosin, HE)染色及關節髁頭厚度測量 .............................................18
3.1.7 統計方法 ........................................ 18
第二節 利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 18
3.2.1 病患顳顎關節液收集 ............................... 18
3.2.2 關節MRI 影像等級分類 ............................. 19
3.2.3 關節液中細胞素之定量 ............................. 19
3.2.4 統計方法 ........................................ 20
第四章 結果 ........................................... 21
第一節 連接蛋白N 端胜肽效益之探討 ....................... 21
4.1.1 連接蛋白N 端胜肽在發炎的細胞環境下之細胞素分析 ...... 21
4.1.2 連接蛋白N 端胜肽在發炎的細胞環境下之基因變化 ........ 22
4.1.3 探討各組組織切片於不同關節位置之變化 ............... 22
4.1.4 大鼠顳顎關節髁頭厚度及整體組織之變化 ............... 25
第二節 利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 26
4.2.1 病患之關節影像學分類 ............................. 26
4.2.2 關節影像學之相關性分析 ........................... 27
4.2.3 關節影像學與關節液中細胞素之相關性分析 ............. 28
第五章 討論 ........................................... 29
第一節 連接蛋白N 端胜肽效益之探討........................ 29
第二節 利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 33
第六章 結論 ........................................... 37
第七章 圖示、表格說明 .................................. 38
圖示 ................................................. 38
圖示1 大鼠顳顎關節注射技術和解剖相對位置 ................. 38
圖示2 7 天內不同組別之大鼠頭圍及關節解剖變化 ............. 39
圖示3 關節組織切片變化 ................................. 41
圖示4 大鼠顳顎關節組織之基因變化 ........................ 42
圖示5 大鼠顳顎關盤之基因變化 ............................ 43
圖示6 大鼠顳顎髁頭之基因變化 ............................ 44
圖示7 大鼠顳顎關節周邊滑膜組織之基因變化 ................. 45
圖示8 24 小時刺激後發炎相關細胞素之表現 .................. 46
圖示9 24、96 小時刺激後抗發炎相關細胞素之表現 ............ 47
圖示10 96 小時刺激後軟骨相關分子之表現 .................. 48
圖示11 24 小時刺激後上皮細胞間質轉化(Epithelial-mesenchymal transition, EMT)相關基因的表現 ........................ 49
圖示12 大鼠顳顎關節遠心處(Lateral)矢狀切面圖 ............ 51
圖示13 大鼠顳顎關節中間位置(Intermediate)矢狀切面圖....... 53
圖示14 大鼠顳顎關節近心處(Medial)矢狀切面圖 ............. 55
圖示15 大鼠顳顎關節髁頭厚度及整體組織之變化 .............. 58
圖示16 顳顎關節障礙症之病患關節髁頭形變分級 .............. 59
圖示17 顳顎關節障礙症之病患關節積液分級 .................. 60
圖示18 顳顎關節障礙症之病患關節積液像素值分類 ............. 61
圖示19 Wilkes 與髁頭骨形變和關節積液分類之相關性 ......... 62
圖示20 細胞素與不同影像分類方式之相關性 .................. 63
圖示21 細胞素與Wilkes 分類的相關性 ...................... 64
圖示22 細胞素與髁頭骨形變分類的相關性 .................... 65
圖示23 細胞素與關節積液分類的相關性 ..................... 66
圖示24 不同影像學分類及關節液細胞素之簡易說明圖 ........... 67
表格 ................................................. 68
表格1 病患樣本之收集步驟 ............................... 68
表格2 不同組別基因表現之比較 ............................ 69
表格4 顳顎關節障礙症之病患相關資料整理 ................... 70
表格5 EMT PCR array-84 個基因 ......................... 71
第八章 參考文獻 ....................................... 73

1. Wadhwa S, Kapila S. TMJ disorders: future innovations in diagnostics and therapeutics. Journal of dental education 2008;72:930-947.
2. Michel G, Tonon T, Scornet D, Cock JM, Kloareg B. The cell wall polysaccharide metabolism of the brown alga Ectocarpus siliculosus. Insights into the evolution of
extracellular matrix polysaccharides in Eukaryotes. The New phytologist 2010;188:82-97.
3. de Moraes LO, Lodi FR, Gomes TS, Marques SR, Oshima CT, Lancellotti CL, et al.Immunohistochemical expression of types I and III collagen antibodies in the temporomandibular joint disc of human foetuses. European journal of histochemistry : EJH 2011;55:e24.
4. Allen KD, Athanasiou KA. Tissue Engineering of the TMJ disc: a review. Tissue engineering 2006;12:1183-1196.
5. Allen KD, Athanasiou KA. Viscoelastic characterization of the porcine temporomandibular joint disc under unconfined compression. Journal of biomechanics 2006;39:312-322.
6. Rosenberg L, Hellmann W, Kleinschmidt AK. Macromolecular models of proteinpolysaccharides from bovine nasal cartilage based on electron microscopic studies. The Journal of biological chemistry 1970;245:4123-4130.
7. Ng L, Grodzinsky AJ, Patwari P, Sandy J, Plaas A, Ortiz C. Individual cartilage aggrecan macromolecules and their constituent glycosaminoglycans visualized via
atomic force microscopy. Journal of structural biology 2003;143:242-257.
8. Willard VP, Kalpakci KN, Reimer AJ, Athanasiou KA. The regional contribution of glycosaminoglycans to temporomandibular joint disc compressive properties. J Biomech Eng 2012;134:011011.
9. Shi S, Grothe S, Zhang Y, O'Connor-McCourt MD, Poole AR, Roughley PJ, et al. Link protein has greater affinity for versican than aggrecan. The Journal of biological
chemistry 2004;279:12060-12066.
10. Mercuri FA, Doege KJ, Arner EC, Pratta MA, Last K, Fosang AJ. Recombinant human aggrecan G1-G2 exhibits native binding properties and substrate specificity for
matrix metalloproteinases and aggrecanase. The Journal of biological chemistry 1999;274:32387-32395.
11. Roughley PJ. The structure and function of cartilage proteoglycans. European cells & materials 2006;12:92-101.
12. Luther F, Layton S, McDonald F. Orthodontics for treating temporomandibular joint (TMJ) disorders. The Cochrane database of systematic reviews 2010:CD006541.
13. Anderson GC, Gonzalez YM, Ohrbach R, Truelove EL, Sommers E, Look JO, et al. The Research Diagnostic Criteria for Temporomandibular Disorders. VI: future directions. Journal of orofacial pain 2010;24:79-88.
14. Wang XD, Kou XX, Mao JJ, Gan YH, Zhou YH. Sustained inflammation induces degeneration of the temporomandibular joint. Journal of dental research 2012;91:499-505.
15. Ferrazzo KL, Osorio LB, Ferrazzo VA. CT Images of a Severe TMJ Osteoarthritis and Differential Diagnosis with Other Joint Disorders. Case reports in dentistry 2013;2013:242685.
16. Kalladka M, Quek S, Heir G, Eliav E, Mupparapu M, Viswanath A. Temporomandibular joint osteoarthritis: diagnosis and long-term conservative management: a topic review. J Indian Prosthodont Soc 2014;14:6-15.
17. Kang SC, Lee DG, Choi JH, Kim ST, Kim YK, Ahn HJ. Association between estrogen receptor polymorphism and pain susceptibility in female temporomandibular joint osteoarthritis patients. International journal of oral and maxillofacial surgery 2007;36:391-394.
18. Xu L, Polur I, Lim C, Servais JM, Dobeck J, Li Y, et al. Early-onset osteoarthritis of mouse temporomandibular joint induced by partial discectomy. Osteoarthritis and
cartilage / OARS, Osteoarthritis Research Society 2009;17:917-922.
19. Tanaka E, Detamore MS, Mercuri LG. Degenerative disorders of the temporomandibular joint: etiology, diagnosis, and treatment. Journal of dental research
2008;87:296-307.
20. Saito T, Tanaka S. Molecular mechanisms underlying osteoarthritis development: Notch and NF-kappaB. Arthritis research & therapy 2017;19:94.
21. Wong SH, Lord JM. Factors underlying chronic inflammation in rheumatoid arthritis. Archivum immunologiae et therapiae experimentalis 2004;52:379-388.
22. Danoff JR, Moss G, Liabaud B, Geller JA. Total knee arthroplasty considerations in rheumatoid arthritis. Autoimmune diseases 2013;2013:185340.
23. Sodhi A, Naik S, Pai A, Anuradha A. Rheumatoid arthritis affecting temporomandibular joint. Contemp Clin Dent 2015;6:124-127.
24. Lin YC, Hsu ML, Yang JS, Liang TH, Chou SL, Lin HY. Temporomandibular joint disorders in patients with rheumatoid arthritis. Journal of the Chinese Medical
Association : JCMA 2007;70:527-534.
25. Edwards CJ, Cooper C. Early environmental factors and rheumatoid arthritis. Clin Exp Immunol 2006;143:1-5.
26. Barzilai O, Ram M, Shoenfeld Y. Viral infection can induce the production of autoantibodies. Curr Opin Rheumatol 2007;19:636-643.
27. Sofat N, Wait R, Robertson SD, Baines DL, Baker EH. Interaction between extracellular matrix molecules and microbial pathogens: evidence for the missing link in
autoimmunity with rheumatoid arthritis as a disease model. Front Microbiol 2014;5:783.
28. Tomita T, Nakase T, Kaneko M, Shi K, Takahi K, Ochi T, et al. Expression of extracellular matrix metalloproteinase inducer and enhancement of the production of matrix metalloproteinases in rheumatoid arthritis. Arthritis and rheumatism 2002;46:373-
378.
29. Kay J, Calabrese L. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology 2004;43 Suppl 3:iii2-iii9.
30. Daheshia M, Yao JQ. The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J Rheumatol 2008;35:2306-2312.
31. Ding L, Hong X, Sun B, Huang Q, Wang X, Liu X, et al. IL-37 is associated with osteoarthritis disease activity and suppresses proinflammatory cytokines production in
synovial cells. Sci Rep 2017;7:11601.
32. Li X, Tian F, Wang F. Rheumatoid arthritis-associated microRNA-155 targets SOCS1 and upregulates TNF-alpha and IL-1beta in PBMCs. International journal of molecular sciences 2013;14:23910-23921.
33. Wojdasiewicz P, Poniatowski LA, Szukiewicz D. The role of inflammatory and antiinflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm
2014;2014:561459.
34. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circulation research
2003;92:827-839.
35. Meszaros E, Malemud CJ. Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. Therapeutic advances in chronic disease 2012;3:219-229.
36. Ishiguro N. [Cartilage degradation in rheumatoid arthritis]. Clin Calcium 2009;19:347-354.
37. Blom AB, van Lent PL, Libregts S, Holthuysen AE, van der Kraan PM, van Rooijen N, et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis and rheumatism 2007;56:147-157.
38. Heard BJ, Martin L, Rattner JB, Frank CB, Hart DA, Krawetz R. Matrix metalloproteinase protein expression profiles cannot distinguish between normal and early osteoarthritic synovial fluid. BMC musculoskeletal disorders 2012;13:126.
39. Sarlis NJ, Chowdrey HS, Stephanou A, Lightman SL. Chronic activation of the hypothalamo-pituitary-adrenal axis and loss of circadian rhythm during adjuvant-induced
arthritis in the rat. Endocrinology 1992;130:1775-1779.
40. Mazzier AG, Laskin DM, Catchpole HR. Adjuvant induced arthritis in the temporomandibular joint of the rat. Arch Pathol 1967;83:543-549.
41. Sano H, Hla T, Maier JA, Crofford LJ, Case JP, Maciag T, et al. In vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and
osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis. J Clin Invest 1992;89:97-108.
42. Dorris SL, Peebles RS, Jr. PGI2 as a regulator of inflammatory diseases. Mediators Inflamm 2012;2012:926968.
43. Dayer JM, Krane SM, Russell RG, Robinson DR. Production of collagenase and prostaglandins by isolated adherent rheumatoid synovial cells. Proc Natl Acad Sci U S A 1976;73:945-949.
44. Bucala R, Ritchlin C, Winchester R, Cerami A. Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. J Exp Med
1991;173:569-574.
45. Kerins C, Carlson D, McIntosh J, Bellinger L. A role for cyclooxygenase II inhibitors in modulating temporomandibular joint inflammation from a meal pattern analysis perspective. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 2004;62:989-995.
46. Harper RP, Kerins CA, Talwar R, Spears R, Hutchins B, Carlson DS, et al. Meal pattern analysis in response to temporomandibular joint inflammation in the rat. Journal
of dental research 2000;79:1704-1711.
47. Kuroki Y, Honda K, Kijima N, Wada T, Arai Y, Matsumoto N, et al. In vivo morphometric analysis of inflammatory condylar changes in rat temporomandibular joint. Oral diseases 2011;17:499-507.
48. Spears R, Dees LA, Sapozhnikov M, Bellinger LL, Hutchins B. Temporal changes in inflammatory mediator concentrations in an adjuvant model of temporomandibular
joint inflammation. Journal of orofacial pain 2005;19:34-40.
49. Bolon B, Stolina M, King C, Middleton S, Gasser J, Zack D, et al. Rodent preclinical models for developing novel antiarthritic molecules: comparative biology and preferred methods for evaluating efficacy. Journal of biomedicine & biotechnology 2011;2011:569068.
50. Shakya AK, Nandakumar KS. Applications of polymeric adjuvants in studying autoimmune responses and vaccination against infectious diseases. Journal of the Royal Society, Interface / the Royal Society 2013;10:20120536.
51. Fujisaki N. Histological evalutation for knee joint and temporomandibular joint (TMJ) in rheumatoid arthritis (RA) model rat. 松本齒學 2008;34:278-297.
52. Bakilan F, Armagan O, Ozgen M, Tascioglu F, Bolluk O, Alatas O. Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial. Eurasian J Med 2016;48:95-101.
53. Wang DH YM, Hsu WE, Hsu ML, Yu LM. Response of the temporomandibular joint tissue of rats to rheumatoid arthritis induction methods. J Dent Sci 2017;12:83–90.
54. Lemos GA, da Silva PLP, Batista AUD, Palomari ET. Experimental model of temporomandibular joint arthritis: Evaluation of contralateral joint and masticatory
muscles. Arch Oral Biol 2018;95:79-88.
55. Poluha RL, Canales GT, Costa YM, Grossmann E, Bonjardim LR, Conti PCR. Temporomandibular joint disc displacement with reduction: a review of mechanisms and
clinical presentation. J Appl Oral Sci 2019;27:e20180433.
56. Machado E, Bonotto D, Cunali PA. Intra-articular injections with corticosteroids and sodium hyaluronate for treating temporomandibular joint disorders: a systematic review. Dental Press J Orthod 2013;18:128-133.
57. Adam M, Deyl Z. Degenerated annulus fibrosus of the intervertebral disc contains collagen type II. Annals of the rheumatic diseases 1984;43:258-263.
58. McKenna LA, Liu H, Sansom PA, Dean MF. An N-terminal peptide from link protein stimulates proteoglycan biosynthesis in human articular cartilage in vitro. Arthritis and rheumatism 1998;41:157-162.
59. Watanabe H, Yamada Y. Mice lacking link protein develop dwarfism and craniofacial abnormalities. Nature genetics 1999;21:225-229.
60. Purcell P, Joo BW, Hu JK, Tran PV, Calicchio ML, O'Connell DJ, et al. Temporomandibular joint formation requires two distinct hedgehog-dependent steps. Proc Natl Acad Sci U S A 2009;106:18297-18302.
61. Ochiai T, Shibukawa Y, Nagayama M, Mundy C, Yasuda T, Okabe T, et al. Indian hedgehog roles in post-natal TMJ development and organization. Journal of dental research 2010;89:349-354.
62. Wang Z, Weitzmann MN, Sangadala S, Hutton WC, Yoon ST. Link protein Nterminal peptide binds to bone morphogenetic protein (BMP) type II receptor and drives
matrix protein expression in rabbit intervertebral disc cells. The Journal of biological chemistry 2013;288:28243-28253.
63. Nguyen Q, Murphy G, Roughley PJ, Mort JS. Degradation of proteoglycan aggregate by a cartilage metalloproteinase. Evidence for the involvement of stromelysin in the generation of link protein heterogeneity in situ. The Biochemical journal 1989;259:61-67.
64. Martin H, Dean M. An N-terminal peptide from link protein is rapidly degraded by chondrocytes, monocytes and B cells. European journal of biochemistry / FEBS
1993;212:87-94.
65. Urban JP, Roberts S. Degeneration of the intervertebral disc. Arthritis research & therapy 2003;5:120-130.
66. Smith LJ, Nerurkar NL, Choi KS, Harfe BD, Elliott DM. Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech 2011;4:31-41.
67. Mwale F, Masuda K, Pichika R, Epure LM, Yoshikawa T, Hemmad A, et al. The efficacy of Link N as a mediator of repair in a rabbit model of intervertebral disc degeneration. Arthritis research & therapy 2011;13:R120.
68. Gawri R, Antoniou J, Ouellet J, Awwad W, Steffen T, Roughley P, et al. Best paper NASS 2013: link-N can stimulate proteoglycan synthesis in the degenerated human
intervertebral discs. European cells & materials 2013;26:107-119; discussion 119.
69. Antoniou J, Wang HT, Alaseem AM, Haglund L, Roughley PJ, Mwale F. The effect of Link N on differentiation of human bone marrow-derived mesenchymal stem cells. Arthritis research & therapy 2012;14:R267.
70. He R, Wang B, Cui M, Xiong Z, Lin H, Zhao L, et al. Link Protein N-Terminal Peptide as a Potential Stimulating Factor for Stem Cell-Based Cartilage Regeneration. Stem Cells Int 2018;2018:3217895.
71. Meyer RA. The Temporomandibular Joint Examination. In: rd, Walker HK, Hall WD, Hurst JW (eds). Clinical Methods: The History, Physical, and Laboratory Examinations. Boston, 1990.
72. Talmaceanu D, Lenghel LM, Bolog N, Hedesiu M, Buduru S, Rotar H, et al. Imaging modalities for temporomandibular joint disorders: an update. Clujul Med 2018;91:280-287.
73. Bag AK, Gaddikeri S, Singhal A, Hardin S, Tran BD, Medina JA, et al. Imaging of the temporomandibular joint: An update. World J Radiol 2014;6:567-582.
74. Talmaceanu D, Lenghel LM, Bolog N, Popa Stanila R, Buduru S, Leucuta DC, et al. High-resolution ultrasonography in assessing temporomandibular joint disc position. Med Ultrason 2018;1:64-70.
75. Westesson PL, Katzberg RW, Tallents RH, Sanchez-Woodworth RE, Svensson SA. CT and MR of the temporomandibular joint: comparison with autopsy specimens. AJR Am J Roentgenol 1987;148:1165-1171.
76. Saini A, Saifuddin A. MRI of osteonecrosis. Clin Radiol 2004;59:1079-1093.
77. Tu KH, Chuang HJ, Lai LA, Hsiao MY. Ultrasound Imaging for Temporomandibular Joint Disc Anterior Displacement. J Med Ultrasound 2018;26:109-110.
78. Kundu H, Basavaraj P, Kote S, Singla A, Singh S. Assessment of TMJ Disorders Using Ultrasonography as a Diagnostic Tool: A Review. J Clin Diagn Res 2013;7:3116-
3120.
79. Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. J Craniomandib
Disord 1992;6:301-355.
80. Wilkes CH. Internal derangements of the temporomandibular joint. Pathological variations. Arch Otolaryngol Head Neck Surg 1989;115:469-477.
81. Ufuk Tatli VM. Internal Derangements of the Temporomandibular Joint: Diagnosis and Management. IntechOpen 2017;chapter 3:47-67.
82. Ahmad M, Hollender L, Anderson Q, Kartha K, Ohrbach R, Truelove EL, et al. Research diagnostic criteria for temporomandibular disorders (RDC/TMD): development
of image analysis criteria and examiner reliability for image analysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:844-860.
83. Larheim TA, Katzberg RW, Westesson PL, Tallents RH, Moss ME. MR evidence of temporomandibular joint fluid and condyle marrow alterations: occurrence in asymptomatic volunteers and symptomatic patients. International journal of oral and maxillofacial surgery 2001;30:113-117.
84. Nogami S, Takahashi T, Ariyoshi W, Yoshiga D, Morimoto Y, Yamauchi K. Increased levels of interleukin-6 in synovial lavage fluid from patients with mandibular
condyle fractures: correlation with magnetic resonance evidence of joint effusion. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 2013;71:1050-1058.
85. Matsumoto K, Honda K, Ohshima M, Yamaguchi Y, Nakajima I, Micke P, et al. Cytokine profile in synovial fluid from patients with internal derangement of the
temporomandibular joint: a preliminary study. Dentomaxillofac Radiol 2006;35:432-441.
86. Afoke A, Hutton WC, Byers PD. Synovial fluid circulation in the hip joint. Med Hypotheses 1984;15:81-86.
87. McCabe PS, Parkes MJ, Maricar N, Hutchinson CE, Freemont A, O'Neill TW, et al. Brief Report: Synovial Fluid White Blood Cell Count in Knee Osteoarthritis: Association With Structural Findings and Treatment Response. Arthritis Rheumatol 2017;69:103-107.
88. Shih CA, Wu KC, Shao CJ, Chern TC, Su WR, Wu PT, et al. Synovial fluid biomarkers: association with chronic rotator cuff tear severity and pain. J Shoulder Elbow
Surg 2018;27:545-552.
89. Nozawa-Inoue K, Amizuka N, Ikeda N, Suzuki A, Kawano Y, Maeda T. Synovial membrane in the temporomandibular joint--its morphology, function and development. Arch Histol Cytol 2003;66:289-306.
90. Joseph P. McCain RHH. Arthroscopic Arthroplasty of the Temporomandibular Joint. Atlas of Operative Oral and Maxillofacial Surgery, First Edition, Chapter 31 2015:271-280.
91. Hui AY, McCarty WJ, Masuda K, Firestein GS, Sah RL. A systems biology approach to synovial joint lubrication in health, injury, and disease. Wiley interdisciplinary reviews Systems biology and medicine 2012;4:15-37.
92. Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 1997;24:365-371.
93. Vangsness CT, Jr., Burke WS, Narvy SJ, MacPhee RD, Fedenko AN. Human knee synovial fluid cytokines correlated with grade of knee osteoarthritis--a pilot study. Bulletin of the NYU hospital for joint diseases 2011;69:122-127.
94. Vos LM, Kuijer R, Huddleston Slater JJ, Stegenga B. Alteration of cartilage degeneration and inflammation markers in temporomandibular joint osteoarthritis occurs
proportionally. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 2013;71:1659-1664.
95. Vos LM, Kuijer R, Huddleston Slater JJ, Bulstra SK, Stegenga B. Inflammation is more distinct in temporomandibular joint osteoarthritis compared to the knee joint. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 2014;72:35-40.
96. Kristensen KD, Alstergren P, Stoustrup P, Kuseler A, Herlin T, Pedersen TK. Cytokines in healthy temporomandibular joint synovial fluid. Journal of oral
rehabilitation 2014;41:250-256.
97. Cherng JH CS, Fang TJ, et al. Surgical-derived oral adipose tissue provides early stage adult stem cells. J Dent Sci 2004;9:10-15.
98. Ahmed N, Mustafa HM, Catrina AI, Alstergren P. Impact of temporomandibular joint pain in rheumatoid arthritis. Mediators Inflamm 2013;2013:597419.
99. De Riu G, Stimolo M, Meloni SM, Soma D, Pisano M, Sembronio S, et al. Arthrocentesis and temporomandibular joint disorders: clinical and radiological results of
a prospective study. Int J Dent 2013;2013:790648.
100. Gonzalez-Garcia R. The current role and the future of minimally invasive temporomandibular joint surgery. Oral Maxillofac Surg Clin North Am 2015;27:69-84.
101. Yano K, Sano T, Okano T. A longitudinal study of magnetic resonance (MR) evidence of temporomandibular joint (TMJ) fluid in patients with TMJ disorders. Cranio
2004;22:64-71.
102. Miana VV, Gonzalez EAP. Adipose tissue stem cells in regenerative medicine. Ecancermedicalscience 2018;12:822.
103. Shi G, Jin Y. Role of Oct4 in maintaining and regaining stem cell pluripotency. Stem Cell Res Ther 2010;1:39.
104. Harvey NT, Hughes JN, Lonic A, Yap C, Long C, Rathjen PD, et al. Response to BMP4 signalling during ES cell differentiation defines intermediates of the ectoderm lineage. J Cell Sci 2010;123:1796-1804.
105. Kubiak M, Ditzel M. A Joint Less Ordinary: Intriguing Roles for Hedgehog Signalling in the Development of the Temporomandibular Synovial Joint. J Dev Biol 2016;4.
106. Cahill CM, Rogers JT. Interleukin (IL) 1beta induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway targeting activator protein-1. The Journal of biological chemistry 2008;283:25900-25912.
107. Lebovic DI, Chao VA, Martini JF, Taylor RN. IL-1beta induction of RANTES (regulated upon activation, normal T cell expressed and secreted) chemokine gene expression in endometriotic stromal cells depends on a nuclear factor-kappaB site in the proximal promoter. J Clin Endocrinol Metab 2001;86:4759-4764.
108. Wang S, Diao N, Lu C, Wu J, Gao Y, Chen J, et al. Evaluation of the diagnostic potential of IP-10 and IL-2 as biomarkers for the diagnosis of active and latent
tuberculosis in a BCG-vaccinated population. PLoS One 2012;7:e51338.
109. Ozeki N, Kawai R, Yamaguchi H, Hiyama T, Kinoshita K, Hase N, et al. IL-1beta-induced matrix metalloproteinase-13 is activated by a disintegrin and metalloprotease-28-regulated proliferation of human osteoblast-like cells. Exp Cell Res 2014;323:165-177.
110. Ozeki N, Yamaguchi H, Kawai R, Hiyama T, Nakata K, Mogi M, et al. Cytokines induce MMP-3-regulated proliferation of embryonic stem cell-derived odontoblast-like cells. Oral diseases 2014;20:505-513.
111. Assirelli E, Pulsatelli L, Dolzani P, Platano D, Olivotto E, Filardo G, et al. Human osteoarthritic cartilage shows reduced in vivo expression of IL-4, a chondroprotective cytokine that differentially modulates IL-1beta-stimulated production of chemokines and matrix-degrading enzymes in vitro. PLoS One 2014;9:e96925.
112. Tuli R, Tuli S, Nandi S, Huang X, Manner PA, Hozack WJ, et al. Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells
involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. The Journal of biological chemistry 2003;278:41227-41236.
113. Tew SR, Murdoch AD, Rauchenberg RP, Hardingham TE. Cellular methods in cartilage research: primary human chondrocytes in culture and chondrogenesis in human
bone marrow stem cells. Methods 2008;45:2-9.
114. Green JD, Tollemar V, Dougherty M, Yan Z, Yin L, Ye J, et al. Multifaceted signaling regulators of chondrogenesis: Implications in cartilage regeneration and tissue engineering. Genes Dis 2015;2:307-327.
115. van Beuningen HM, van der Kraan PM, Arntz OJ, van den Berg WB. In vivo protection against interleukin-1-induced articular cartilage damage by transforming
growth factor-beta 1: age-related differences. Annals of the rheumatic diseases 1994;53:593-600.
116. Maldonado M, Nam J. The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis. Biomed Res Int 2013;2013:284873.
117. Fu P, Cong R, Chen S, Zhang L, Ding Z, Zhou Q, et al. [Conditions of Synovial Mesenchymal Stem Cells Differentiating into Fibrocartilage Cells]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2015;29:81-91.
118. Passler T, Chamorro MF, Riddell KP, Edmondson MA, van Santen E, Cray C, et al. Evaluation of methods to improve the diagnosis of systemic inflammation in alpacas. J Vet Intern Med 2013;27:970-976.
119. Rai MF, Graeve T, Twardziok S, Schmidt MF. Evidence for regulated interleukin-4 expression in chondrocyte-scaffolds under in vitro inflammatory conditions. PLoS One 2011;6:e25749.
120. Somarelli JA, Shetler S, Jolly MK, Wang X, Bartholf Dewitt S, Hish AJ, et al. Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial
Expression of MicroRNA 200s and GRHL2. Mol Cell Biol 2016;36:2503-2513.
121. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014;15:178-196.
122. Zhou S, Shen Y, Wang L, Li P. Epithelial-mesenchymal transition and mesenchymalepithelial transition response during differentiation of growth-plate chondrocytes in
endochondral ossification. Int J Clin Exp Med 2015;8:12076-12085.
123. Chen J, Han Q, Pei D. EMT and MET as paradigms for cell fate switching. J Mol Cell Biol 2012;4:66-69.
124. Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009;119:1417-1419.
125. Ricciardi M, Zanotto M, Malpeli G, Bassi G, Perbellini O, Chilosi M, et al. Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits
mesenchymal stromal cell-like immune-modulatory properties in cancer cells. Br J Cancer 2015;112:1067-1075.
126. Rodrigues-Pinto R, Berry A, Piper-Hanley K, Hanley N, Richardson SM, Hoyland JA. Spatiotemporal analysis of putative notochordal cell markers reveals CD24 and keratins 8, 18, and 19 as notochord-specific markers during early human intervertebral disc development. J Orthop Res 2016;34:1327-1340.
127. Katoh M, Katoh M. Identification and characterization of human SNAIL3 (SNAI3) gene in silico. Int J Mol Med 2003;11:383-388.
128. Alam H, Sehgal L, Kundu ST, Dalal SN, Vaidya MM. Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells. Mol Biol Cell 2011;22:4068-4078.
129. Simon DP, Giordano TJ, Hammer GD. Upregulated JAG1 enhances cell proliferation in adrenocortical carcinoma. Clin Cancer Res 2012;18:2452-2464.
130. He Z, Jiang J, Kokkinaki M, Dym M. Nodal signaling via an autocrine pathway promotes proliferation of mouse spermatogonial stem/progenitor cells through Smad2/3 and Oct-4 activation. Stem Cells 2009;27:2580-2590.
131. Fisher MC, Clinton GM, Maihle NJ, Dealy CN. Requirement for ErbB2/ErbB signaling in developing cartilage and bone. Dev Growth Differ 2007;49:503-513.
132. Nawachi K, Inoue M, Kubota S, Nishida T, Yosimichi G, Nakanishi T, et al. Tyrosine kinase-type receptor ErbB4 in chondrocytes: interaction with connective tissue growth factor and distribution in cartilage. FEBS Lett 2002;528:109-113.
133. Esquivies L, Blackler A, Peran M, Rodriguez-Esteban C, Izpisua Belmonte JC, Booker E, et al. Designer nodal/BMP2 chimeras mimic nodal signaling, promote
chondrogenesis, and reveal a BMP2-like structure. The Journal of biological chemistry 2014;289:1788-1797.
134. Weber CE, Li NY, Wai PY, Kuo PC. Epithelial-mesenchymal transition, TGF-beta, and osteopontin in wound healing and tissue remodeling after injury. J Burn Care Res 2012;33:311-318.
135. Dean MF, Sansom P. Link peptide cartilage growth factor is degraded by membrane proteinases. The Biochemical journal 2000;349:473-479.
136. Abou Elkhier MT MN, Mourad MI. Therapeutic Potential of Intra-Articular Injection of Bone Marrow Mesenchymal Stem Cells on Tempromandibular Joints' Induced Osteoarthritis. An Experimental Study. J Dent Oral Biol 2018;3:1150.
137. Nascimento GC, Rizzi E, Gerlach RF, Leite-Panissi CR. Expression of MMP-2 and MMP-9 in the rat trigeminal ganglion during the development of temporomandibular
joint inflammation. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [et al] 2013;46:956-967.
138. I Mizoguchi NT, Y Nakao. Growth of the mandible and biological characteristics of the mandibular condylar cartilage. Japanese Dental Science Review 2013;49:139-150.
139. Embree MC, Chen M, Pylawka S, Kong D, Iwaoka GM, Kalajzic I, et al. Exploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury. Nat Commun 2016;7:13073.
140. Hirata FH, Guimaraes AS, Oliveira JX, Moreira CR, Ferreira ET, Cavalcanti MG. Evaluation of TMJ articular eminence morphology and disc patterns in patients with disc displacement in MRI. Braz Oral Res 2007;21:265-271.
141. Park HN, Kim KA, Koh KJ. Relationship between pain and effusion on magnetic resonance imaging in temporomandibular disorder patients. Imaging Sci Dent
2014;44:293-299.
142. Paniagua B, Pascal L, Prieto J, Vimort JB, Gomes L, Yatabe M, et al. Diagnostic Index: An open-source tool to classify TMJ OA condyles. Proc SPIE Int Soc Opt Eng
2017;10137.
143. Al-Hashmi A, Al-Azri A, Al-Ismaily M, Goss AN. Temporomandibular disorders in patients with mandibular fractures: a preliminary comparative case-control study between South Australia and Oman. International journal of oral and maxillofacial surgery 2011;40:1369-1372.
144. Dimitroulis G. A new surgical classification for temporomandibular joint disorders. International journal of oral and maxillofacial surgery 2013;42:218-222.
145. Suenaga S, Nagayama K, Nagasawa T, Indo H, Majima HJ. The usefulness of diagnostic imaging for the assessment of pain symptoms in temporomandibular disorders. Jpn Dent Sci Rev 2016;52:93-106.
146. Fu KY, Li YW, Zhang ZK, Ma XC. Osteonecrosis of the mandibular condyle as a precursor to osteoarthrosis: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2009;107:e34-38.
147. Segami N, Nishimura M, Kaneyama K, Miyamaru M, Sato J, Murakami KI. Does joint effusion on T2 magnetic resonance images reflect synovitis? Comparison of arthroscopic findings in internal derangements of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:341-345.
148. Larheim TA, Westesson PL, Hicks DG, Eriksson L, Brown DA. Osteonecrosis of the temporomandibular joint: correlation of magnetic resonance imaging and histology.
Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 1999;57:888-898; discussion 899.
149. Oliveira JX, Rosa JA, Dutra ME, Santos KC, Gil C. Assessing joint effusion and bone changes of the head of the mandible in MR images of symptomatic patients. Braz
Oral Res 2013;27:37-41.
150. Alstergren P, Ernberg M, Kvarnstrom M, Kopp S. Interleukin-1beta in synovial fluid from the arthritic temporomandibular joint and its relation to pain, mobility, and anterior open bite. Journal of oral and maxillofacial surgery : official journal of the American
Association of Oral and Maxillofacial Surgeons 1998;56:1059-1065; discussion 1066.
151. Kim YK, Kim SG, Kim BS, Lee JY, Yun PY, Bae JH, et al. Analysis of the cytokine profiles of the synovial fluid in a normal temporomandibular joint: preliminary study. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery 2012;40:e337-341.
152. Aghabeigi B, Cintra N, Meghji S, Evans A, Crean SJ. Temporomandibular joint synovial fluid sampling: estimation of dilution factor using calcium ion concentration. International journal of oral and maxillofacial surgery 2002;31:646-649.
153. MIG Campos PC SL. Inflammatory cytokines activity in temporomandibular joint disorders: a review of literature. Braz J Oral Sci 2006;5:1054–1062.
154. Wakita T, Mogi M, Kurita K, Kuzushima M, Togari A. Increase in RANKL: OPG ratio in synovia of patients with temporomandibular joint disorder. Journal of dental research 2006;85:627-632.
155. Vernal R, Velasquez E, Gamonal J, Garcia-Sanz JA, Silva A, Sanz M. Expression of proinflammatory cytokines in osteoarthritis of the temporomandibular joint. Arch Oral Biol 2008;53:910-915.
156. Monasterio G, Castillo F, Rojas L, Cafferata EA, Alvarez C, Carvajal P, et al. Th1/Th17/Th22 immune response and their association with joint pain, imagenological bone loss, RANKL expression and osteoclast activity in temporomandibular joint osteoarthritis: A preliminary report. Journal of oral rehabilitation 2018;45:589-597.
157. Kaneyama K, Segami N, Sun W, Sato J, Fujimura K. Levels of soluble cytokine factors in temporomandibular joint effusions seen on magnetic resonance images. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:411-418.
158. Kaneyama K, Segami N, Sun W, Sato J, Fujimura K. Analysis of tumor necrosis factor-alpha, interleukin-6, interleukin-1beta, soluble tumor necrosis factor receptors I and II, interleukin-6 soluble receptor, interleukin-1 soluble receptor type II, interleukin-1
receptor antagonist, and protein in the synovial fluid of patients with temporomandibular joint disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:276-284.
159. Bendre MS, Montague DC, Peery T, Akel NS, Gaddy D, Suva LJ. Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased
osteolysis of metastatic bone disease. Bone 2003;33:28-37.
160. Nishimura M, Segami N, Kaneyama K, Suzuki T, Miyamaru M. Proinflammatory cytokines and arthroscopic findings of patients with internal derangement and osteoarthritis of the temporomandibular joint. Br J Oral Maxillofac Surg 2002;40:68-71.
161. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 2006;80:227-236.
162. TK NO. Molecular aspects in inflammatory events of temporomandibular joint: microarray-based identification of mediators. Jpn Dent Sci Rev 2015;51:10–24.