The aim of this study was to examine interleukin-6 production and the activation of signal transducer and activator of transcription-3 (STAT3) in ruptured rotator cuff tendon. Specimens of ruptured rotator cuff tendons were analysed using real-time reverse transcriptase polymerase chain reaction, Western blotting and immunohistochemistry. Specimens of co-existing inflammatory subacromial synovia were examined for comparison. The level of interleukin-6 messenger RNA was increased in ruptured rotator cuff tendon as well as in subacromial synovium. Western blot analysis showed constitutive production of activated, phosphorylated STAT3 in ruptured rotator cuff tendon and co-existing subacromial synovium. Immunohistochemical examination detected cells producing interleukin-6, interleukin-6 receptor and phosphorylated STAT3 in ruptured rotator cuff tendon, mainly in proliferative vessels and, to a lesser extent, in tendon fibroblasts around the vessels. This study demonstrates that activation of STAT3 induced by interleukin-6 is promoted mainly by proliferative vessels in ruptured rotator cuff tendon.
GotohMHamadaKYamakawaHYanagisawaKNakamuraMYamazakiH: Interleukin-1-induced subacromial synovitis and shoulder pain in rotator cuff diseases. Rheumatology (Oxford)2001; 40: 995–1001.
2.
NeerCS2nd: Anterior acromioplasty for the chronic impingement syndrome of the shoulder: A preliminary report. J Bone Joint Surg Am1972; 54: 41–50.
3.
SoiferTBLevyHJSoiferFMKleinbartFVigoritaVBrykE: Neurohistology of the subacromial space. Arthroscopy1996; 12: 182–186.
4.
TomitaYOzakiJSakuraiGKandoTNakagakiKTamaiS: Neurohistology of the subacromial bursa in rotator cuff tear. J Orthop Sci1997; 2: 295–300.
5.
VangsnessCTJrEnnisMTaylorJGAtkinsonR: Neural anatomy of the glenohumeral ligaments, labrum, and subacromial bursa. Arthroscopy1995; 11: 180–184.
6.
MehtaSGimbelJASoslowskyLJ: Etiologic and pathogenetic factors for rotator cuff tendinopathy. Clin Sports Med2003; 22: 791–812.
7.
HashimotoTNobuharaKHamadaT: Pathologic evidence of degeneration as a primary cause of rotator cuff tear. Clin Orthop Relat Res2003; 415: 111–120.
8.
KannusPJozsaL: Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J Bone Joint Surg Am1991; 73: 1507–1525.
9.
SharmaPMaffulliN: Tendon injury and tendinopathy: Healing and repair. J Bone Joint Surg Am2005; 87: 187–202.
10.
KhanKMCookJLBonarFHarcourtPAstromM: Histopathology of common tendinopathies. Update and implications for clinical management. Sports Med1999; 27: 393–408.
11.
IrelandDHarrallRLCurryVHollowayGHackneyRHazlemanBL: Multiple changes in gene expression in chronic human Achilles tendinopathy. Matrix Biol2001; 20: 159–169.
12.
KhanKMCookJLKannusPMaffulliNBonarSF: Time to abandon the ‘tendonitis’ myth. BMJ2002; 324: 626–627.
13.
RileyG: The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford)2004; 43: 131–142.
14.
HodgeDRHurtEMFarrarWL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer2005; 41: 2502–2512.
15.
LangbergHOlesenJLGemmerCKjaerM: Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans. J Physiol2002; 542: 985–990.
16.
LangbergHSkovgaardDKaramouzisMBulowJKjaerM: Metabolism and inflammatory mediators in the peritendinous space measured by microdialysis during intermittent isometric exercise in humans. J Physiol1999; 515: 919–927.
17.
LangbergHSkovgaardDPetersenLJBulowJKjaerM: Type I collagen synthesis and degradation in peritendinous tissue after exercise determined by microdialysis in humans. J Physiol1999; 15: 299–306.
18.
SkutekMvan GriensvenMZeichenJBrauerNBoschU: Cyclic mechanical stretching enhances secretion of interleukin 6 in human tendon fibroblasts. Knee Surg Sports Traumatol Arthrosc2001; 9: 322–326.
19.
NakamaLHKingKBAbrahamssonSRempelDM: Evidence of tendon microtears due to cyclical loading in an in vivo tendinopathy model. J Orthop Res2005; 23: 1199–1205.
20.
HodgeDRHurtEMFarrarWL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer2005; 41: 2502–2512.
21.
DarnellJEJr: STATs and gene regulation. Science1997; 277: 1630–1635.
22.
LeeCLimHKSakongJLeeYSKimJRBaekSH: Janus kinase-signal transducer and activator of transcription mediates phosphatidic acid-induced interleukin (IL)-1 beta and IL-6 production. Mol Pharmacol2006; 69: 1041–1047.
23.
BlaineTAKimYSVoloshinIChenDMurakamiKChangSS: The molecular pathophysiology of subacromial bursitis in rotator cuff disease. J Shoulder Elbow Surg2005; 14: 84S–89S.
24.
VoloshinIGelinasJMaloneyMDO'KeefeRJBiglianiLUBlaineTA: Proinflammatory cytokines and metalloproteases are expressed in the subacromial bursa in patients with rotator cuff disease. Arthroscopy2005; 21:1076.
25.
Ben-ShaharYRobichonASokolowskiMBRobinsonGE: Influence of gene action across different time scales on behavior. Science2002; 296: 741–744.
Hilfiker-KleinerDHilfikerAFuchsMKaminskiKSchaeferASchiefferB: Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res2004; 95: 187–195.
31.
NewmanJSAdlerRSBudeRORubinJM: Detection of soft-tissue hyperemia: Value of power Doppler sonography. Am J Roentgenol1994; 163: 385–389.
32.
Mohana-BorgesAVChungCBResnickD: MR imaging and MR arthrography of the postoperative shoulder: Spectrum of normal and abnormal findings. Radiographics2004; 24: 69–85.
33.
FreelandAETucciMABarbieriRAAngelMFNickTG: Biochemical evaluation of serum and flexor tenosynovium in carpal tunnel syndrome. Microsurgery2002; 22: 378–385.
34.
NomaHFunatsuHYamasakiMTsukamotoHMimuraTSoneT: Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6. Am J Ophthalmol2005; 140: 256–261.
35.
BjurDAlfredsonHForsgrenS: The innervation pattern of the human Achilles tendon: Studies of the normal and tendinosis tendon with markers for general and sensory innervation. Cell Tissue Res2005; 320: 201–206.
36.
AzzolinaABongiovanniALampiasiN: Substance P induces TNF-α and IL-6 production through NFκB in peritoneal mast cells. Biochim Biophys Acta2003; 1643: 75–83.
37.
OhbergLAlfredsonH: Ultrasound guided sclerosis of neovessels in painful chronic Achilles tendinosis: Pilot study of a new treatment. Br J Sports Med2002; 36: 173–175.
38.
ShoudaTYoshidaTHanadaTWakiokaTOishiMMiyoshiK: Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest2001; 108: 1781–1788.
39.
SuzukiAHanadaTMitsuyamaKYoshidaTKamizonoSHoshinoT: CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med2001; 193: 471–481.
