Influence of Smoking on the Expression of Genes and Proteins Related to Fat Infiltration, Inflammation, and Fibrosis in the Rotator Cuff Muscles of Patients With Chronic Rotator Cuff Tears: A Pilot Study


      To evaluate the altered gene and protein expression patterns in the rotator cuff muscles of smokers and non-smokers with rotator cuff tears and to identify the smoking-associated key genetic factor(s) involved in rotator cuff muscle physiology.


      Twenty-four samples of rotator cuff muscle from 12 current heavy smokers (mean age 61.8 ± 5.1 years) and age- and sex-matched 12 non-smokers (mean age 61.8 ± 6.9 years) with medium-sized tears were acquired during arthroscopic surgery. As a statistical method, the propensity score matching technique was used to select control group by 1:1 matching for age and sex. Inclusion criteria were patients who underwent arthroscopic repair for medium-sized full-thickness rotator cuff tears and those that were current smokers with a smoking history >20 packs/year. Patients lacking medium-sized tears, those with recent steroid injection history, isolated subscapularis tear, preoperative stiff shoulder, acute traumatic tear, or previous surgery on the same shoulder, or those that declined to participate were excluded. Alterations in the expression of genes and proteins associated with myogenesis, inflammation, adipogenesis, and muscle fibrosis were compared between smokers and non-smokers with reverse-transcription quantitative polymerase chain reaction, western blotting, and immunohistochemistry.


      Histologic analysis revealed increased inflammation and remarkable fat accumulation and fibrogenesis in the rotator cuff muscle from smokers compared with that from non-smokers. The mRNA expression levels of inflammatory high mobility group box 1 (HMGB1; P = .043), adipogenic CCAAT/enhancer-binding protein alpha (P = .046) and peroxisome proliferator-activated receptor gamma (PPARγ; P = .048), myogenic differentiation 1 (P = .032), fibrogenic alpha-smooth muscle actin (α-SMA; P = .033), and metalloproteinase 9 (P = .036) were significantly greater in samples from smokers than from non-smokers. A correlation was observed between gene and protein expression of HMGB1 (P = .034), PPARγ (P = .021), and α-SMA (P = .021).


      Smokers with rotator cuff tears showed high inflammation, large fat infiltration, and fibrosis in rotator cuff muscle that is associated with the increased expression of HMGB1, PPARγ, and α-SMA, respectively.

      Level of Evidence

      Case control study (Prognostic level III)
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        • West R.
        Tobacco smoking: Health impact, prevalence, correlates and interventions.
        Psychol Health. 2017; 32: 1018-1036
        • Al-Bashaireh A.M.
        • Haddad L.G.
        • Weaver M.
        • Kelly D.L.
        • Chengguo X.
        • Yoon S.
        The effect of tobacco smoking on musculoskeletal health: A systematic review.
        J Environ Public Health. 2018; 2018: 4184190
        • Talhout R.
        • Schulz T.
        • Florek E.
        • van Benthem J.
        • Wester P.
        • Opperhuizen A.
        Hazardous compounds in tobacco smoke.
        Int J Environ Res Public Health. 2011; 8: 613-628
        • Degens H.
        • Gayan-Ramirez G.
        • van Hees H.W.
        Smoking-induced skeletal muscle dysfunction: From evidence to mechanisms.
        Am J Respir Critical Care Med. 2015; 191: 620-625
        • Galatz L.M.
        • Silva M.J.
        • Rothermich S.Y.
        • Zaegel M.A.
        • Havlioglu N.
        • Thomopoulos S.
        Nicotine delays tendon-to-bone healing in a rat shoulder model.
        J Bone Joint Surg Am. 2006; 88: 2027-2034
        • Baumgarten K.M.
        • Gerlach D.
        • Galatz L.M.
        • et al.
        Cigarette smoking increases the risk for rotator cuff tears.
        Clin Orthop Rel Res. 2010; 468: 1534-1541
        • Santiago-Torres J.
        • Flanigan D.C.
        • Butler R.B.
        • Bishop J.Y.
        The effect of smoking on rotator cuff and glenoid labrum surgery: A systematic review.
        Am J Sports Med. 2015; 43: 745-751
        • Naimark M.
        • Robbins C.B.
        • Gagnier J.J.
        • et al.
        Impact of smoking on patient outcomes after arthroscopic rotator cuff repair.
        BMJ Open Sport Exerc Med. 2018; 4: e000416
        • Ichinose R.
        • Sano H.
        • Kishimoto K.N.
        • Sakamoto N.
        • Sato M.
        • Itoi E.
        Alteration of the material properties of the normal supraspinatus tendon by nicotine treatment in a rat model.
        Acta Orthop. 2010; 81: 634-638
        • Lundgreen K.
        • Lian ØB Scott A.
        • Nassab P.
        • Fearon A.
        • Engebretsen L.
        Rotator cuff tear degeneration and cell apoptosis in smokers versus nonsmokers.
        Arthroscopy. 2014; 30: 936-941
        • Park J.H.
        • Oh K.S.
        • Kim T.M.
        • et al.
        Effect of smoking on healing failure after rotator cuff repair.
        Am J Sports Med. 2018; (363546518789691)
        • Ma J.
        • Piuzzi N.S.
        • Muschler G.F.
        • Iannotti J.P.
        • Ricchetti E.T.
        • Derwin K.A.
        Biomarkers of rotator cuff disease severity and repair healing.
        JBJS Rev. 2018; 6: e9
        • McCarthy C.G.
        • Webb R.C.
        The toll of the gridiron: Damage-associated molecular patterns and hypertension in American football.
        FASEB J. 2016; 30: 34-40
        • Scaffidi P.
        • Misteli T.
        • Bianchi M.E.
        Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.
        Nature. 2002; 418: 191-195
        • Yang H.
        • Wang H.
        • Chavan S.S.
        • Andersson U.
        High Mobility Group Box Protein 1 (HMGB1): The prototypical endogenous danger molecule.
        Mol Med. 2015; 21 (suppl 1): S6-s12
        • Gladstone J.N.
        • Bishop J.Y.
        • Lo I.K.
        • Flatow E.L.
        Fatty infiltration and atrophy of the rotator cuff do not improve after rotator cuff repair and correlate with poor functional outcome.
        Am J Sports Med. 2007; 35: 719-728
        • Frey E.
        • Regenfelder F.
        • Sussmann P.
        • et al.
        Adipogenic and myogenic gene expression in rotator cuff muscle of the sheep after tendon tear.
        J Orthop Res. 2009; 27: 504-509
        • Uezumi A.
        • Ito T.
        • Morikawa D.
        • et al.
        Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle.
        J Cell Sci. 2011; 124: 3654-3664
        • Perry R.L.
        • Rudnick M.A.
        Molecular mechanisms regulating myogenic determination and differentiation.
        Front Biosci. 2000; 5: D750-767
        • Rudnicki M.A.
        • Schnegelsberg P.N.
        • Stead R.H.
        • Braun T.
        • Arnold H.H.
        • Jaenisch R.
        MyoD or Myf-5 is required for the formation of skeletal muscle.
        Cell. 1993; 75: 1351-1359
        • Megeney L.A.
        • Kablar B.
        • Garrett K.
        • Anderson J.E.
        • Rudnicki M.A.
        MyoD is required for myogenic stem cell function in adult skeletal muscle.
        Genes Dev. 1996; 10: 1173-1183
        • Berkes C.A.
        • Tapscott S.J.
        MyoD and the transcriptional control of myogenesis.
        Semin Cell Dev Biol. 2005; 16: 585-595
        • Goutallier D.
        • Postel J.M.
        • Bernageau J.
        • Lavau L.
        • Voisin M.C.
        Fatty muscle degeneration in cuff ruptures. Pre- and postoperative evaluation by CT scan.
        Clin Orthop Rel Res. 1994; : 78-83
        • Khazzam M.
        • Kuhn J.E.
        • Mulligan E.
        • et al.
        Magnetic resonance imaging identification of rotator cuff retears after repair: Interobserver and intraobserver agreement.
        Am J Sports Med. 2012; 40: 1722-1727
        • Lippe J.
        • Spang J.T.
        • Leger R.R.
        • Arciero R.A.
        • Mazzocca A.D.
        • Shea K.P.
        Inter-rater agreement of the Goutallier, Patte, and Warner classification scores using preoperative magnetic resonance imaging in patients with rotator cuff tears.
        Arthroscopy. 2012; 28: 154-159
        • Oh J.H.
        • Kim S.H.
        • Choi J.A.
        • Kim Y.
        • Oh C.H.
        Reliability of the grading system for fatty degeneration of rotator cuff muscles.
        Clin Orthop Rel Res. 2010; 468: 1558-1564
        • Spencer Jr., E.E.
        • Dunn W.R.
        • Wright R.W.
        • et al.
        Interobserver agreement in the classification of rotator cuff tears using magnetic resonance imaging.
        Am J Sports Med. 2008; 36: 99-103
        • Stampfli M.R.
        • Anderson G.P.
        How cigarette smoke skews immune responses to promote infection, lung disease and cancer.
        Nat Rev Immunol. 2009; 9: 377-384
        • Neves C.D.
        • Lacerda A.C.
        • Lage V.K.
        • et al.
        Oxidative stress and skeletal muscle dysfunction are present in healthy smokers.
        Braz J Med Biol Res. 2016; 49: e5512
        • Madani A.
        • Alack K.
        • Richter M.J.
        • Kruger K.
        Immune-regulating effects of exercise on cigarette smoke-induced inflammation.
        J Inflamm Res. 2018; 11: 155-167
        • Pouwels S.D.
        • Hesse L.
        • Faiz A.
        • et al.
        Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD.
        Am J Physiol Lung Cell Mol Physiol. 2016; 311: L881-l892
        • Wynn T.A.
        Cellular and molecular mechanisms of fibrosis.
        J Pathol. 2008; 214: 199-210
        • Bochaton-Piallat M.L.
        • Gabbiani G.
        • Hinz B.
        The myofibroblast in wound healing and fibrosis: answered and unanswered questions.
        F1000Research. 2016; : 5
        • Bishop J.Y.
        • Santiago-Torres J.E.
        • Rimmke N.
        • Flanigan D.C.
        Smoking predisposes to rotator cuff pathology and shoulder dysfunction: A systematic review.
        Arthroscopy. 2015; 31: 1598-1605
        • Harris J.D.
        • Brand J.C.
        • Cote M.P.
        • Faucett S.C.
        • Dhawan A.
        Research pearls: The significance of statistics and perils of pooling. Part 1: Clinical versus statistical significance.
        Arthroscopy. 2017; 33: 1102-1112

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