Rat models of frozen shoulder: Classification and evaluation

Abstract

Frozen shoulder (FS), also known as adhesive capsulitis, is a condition that causes contraction and stiffness of the shoulder joint capsule. The main symptoms are persistent shoulder pain and a limited range of motion in all directions. These symptoms and poor prognosis affect people’s physical health and quality of life. Currently, the specific mechanisms of FS remain unclear, and there is variability in treatment methods and their efficacy. Additionally, the early symptoms of FS are difficult to distinguish from those of other shoulder diseases, complicating early diagnosis and treatment. Therefore, it is necessary to develop and utilize animal models to understand the pathogenesis of FS and to explore treatment strategies, providing insights into the prevention and treatment of human FS. This paper res the rat models available for FS research, including external immobilization models, surgical internal immobilization models, injection modeling models, and endocrine modeling models. It introduces the basic procedures for these models and compares and analyzes the advantages, disadvantages, and applicability of each modeling method. Finally, our paper summarizes the common methods for evaluating FS rat models.

Keywords

endocrine modeling / injection / rat model / surgical internal immobilization

References

[1] Millar NL, Meakins A, Struyf F, et al. Frozen shoulder. Nat Rev Dis Primers. 2022;8(1):59.

[2] Leafblad N, Mizels J, Tashjian R, Chalmers P. Adhesive capsulitis. Phys Med Rehabil Clin N Am. 2023;34(2):453-468.

[3] Lho YM, Ha E, Cho CH, et al. Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder. J Shoulder Elb Surg. 2013;22(5):666-672.

[4] Rodeo SA, Hannafin JA, Tom J, Warren RF, Wickiewicz TL. Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder. J Orthop Res. 1997;15(3):427-436.

[5] Hsu JE, Anakwenze OA, Warrender WJ, Abboud JA. Current review of adhesive capsulitis. J Shoulder Elb Surg. 2011;20(3):502-514.

[6] Hand GCR, Athanasou NA, Matthews T, Carr AJ. The pathology of frozen shoulder. J Bone Joint Surg Br. 2007;89B(7):928-932.

[7] Mullett H, Byrne D, Colville J. Adhesive capsulitis: human fibroblast response to shoulder joint aspirate from patients with stage II disease. J Shoulder Elb Surg. 2007;16(3):290-294.

[8] Tamai K, Akutsu M, Yano Y. Primary frozen shoulder: brief review of pathology and imaging abnormalities. J Orthop Sci. 2014;19(1):1-5.

[9] Kwaees TA, Charalambous CP. Rates of surgery for frozen shoulder: an experience in England. Muscles Ligaments Tendons J. 2015;5(4):276-279.

[10] Harris G, Bou-Haidar P, Harris C. Adhesive capsulitis: review of imaging and treatment. J Med Imaging Radiat Oncol. 2013;57(6):633-643.

[11] Dias R, Cutts S, Massoud S. Frozen shoulder. BMJ. 2005;331(7530):1453-1456.

[12] Zuckerman JD, Rokito A. Frozen shoulder: a consensus definition. J Shoulder Elb Surg. 2011;20(2):322-325.

[13] de la Serna D, Navarro-Ledesma S, Alayón F, López E, Pruimboom L. A comprehensive of Frozen shoulder: a mystery syndrome. Front Med (Lausanne). 2021;8:663703.

[14] Le HV, Lee SJ, Nazarian A, Rodriguez EK. Adhesive capsulitis of the shoulder: review of pathophysiology and current clinical treatments. Should Elb. 2017;9(2):75-84.

[15] Juel NG, Brox JI, Brunborg C, Holte KB, Berg TJ. Very high prevalence of Frozen shoulder in patients with type 1 diabetes of ≥45 Years’ duration: the Dialong shoulder study. Arch Phys Med Rehabil. 2017;98(8):1551-1559.

[16] Alhashimi RAH. Analytical observational study of Frozen shoulder among patients with diabetes mellitus. Joints. 2018;6(3):141-144.

[17] Sun G, Li Q, Yin Y, Fu W, He K, Pen X. Risk factors and predictive models for frozen shoulder. Sci Rep. 2024;14(1):15261.

[18] Wang JY, Liaw CK, Huang CC, Liou TH, Lin HW, Huang SW. Hyperlipidemia is a risk factor of adhesive capsulitis: real-world evidence using the Taiwanese National Health Insurance Research Database. Orthop J Sports Med. 2021;9(4):2325967120986808.

[19] Spinnato P, Masuzzo O, Tuè G, et al. A novel ultrasound-guided interventional procedure for the combined treatment of rotator cuff calcific tendinopathy complicated with adhesive capsulitis: the ‘Rizzoli’ technique. Acad Radiol. 2023;30(10):2437-2438.

[20] Piso R, Pistoia F, Zaottini F, et al. Adhesive capsulitis of the shoulder: current concepts on the diagnostic work-up and evidence-based protocol for radiological evaluation. Diagnostics (Basel). 2023;13(22):3410.

[21] Mertens MG, Meeus M, Verborgt O, et al. An overview of effective and potential new conservative interventions in patients with frozen shoulder. Rheumatol Int. 2022;42(6):925-936.

[22] Struyf F, Meeus M. Current evidence on physical therapy in patients with adhesive capsulitis: what are we missing? Clin Rheumatol. 2014;33(5):593-600.

[23] Song A, Higgins LD, Newman J, Jain NB. Glenohumeral corticosteroid injections in adhesive capsulitis: a systematic search and review. PM R. 2014;6(12):1143-1156.

[24] Johnson AJ, Godges JJ, Zimmerman GJ, Ounanian LL. The effect of anterior versus posterior glide joint mobilization on external rotation range of motion in patients with shoulder adhesive capsulitis. J Orthop Sports Phys Ther. 2007;37(3):88-99.

[25] Challoumas D, Biddle M, McLean M, Millar NL. Comparison of treatments for Frozen shoulder: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(12):e2029581.

[26] Kuhn I, Erber B, Goller SS. Adhesive capsulitis. Radiologie (Heidelb). 2024;64(2):119-124.

[27] Kim DH, Kim YS, Kim BS, Sung DH, Song KS, Cho CH. Is frozen shoulder completely resolved at 2 years after the onset of disease? J Orthop Sci. 2020;25(2):224-228.

[28] Hand C, Clipsham K, Rees JL, Carr AJ. Long-term outcome of frozen shoulder. J Shoulder Elb Surg. 2008;17(2):231-236.

[29] Ryan V, Brown H, Minns Lowe CJ, Lewis JS. The pathophysiology associated with primary (idiopathic) frozen shoulder: a systematic review. BMC Musculoskelet Disord. 2016;17(1):340.

[30] Neviaser AS, Hannafin JA. Adhesive capsulitis: a review of current treatment. Am J Sports Med. 2010;38(11):2346-2356.

[31] Hannafin JA, Chiaia TA. Adhesive capsulitis. A treatment approach. Clin Orthop Relat Res. 2000;372:95-109.

[32] Robinson CM, Seah KT, Chee YH, Hindle P, Murray IR. Frozen shoulder. J Bone Joint Surg Br. 2012;94(1):1-9.

[33] Favejee MM, Huisstede BM, Koes BW. Frozen shoulder: the effectiveness of conservative and surgical interventions—systematic review. Br J Sports Med. 2011;45(1):49-56.

[34] Jung JY, Jee WH, Chun HJ, Kim YS, Chung YG, Kim JM. Adhesive capsulitis of the shoulder: evaluation with MR arthrography. Eur Radiol. 2006;16(4):791-796.

[35] Park S, Lee DH, Yoon SH, Lee HY, Kwack KS. Evaluation of adhesive capsulitis of the shoulder with fat-suppressed T2-weighted MRI: association between clinical features and MRI findings. AJR Am J Roentgenol. 2016;207(1):135-141.

[36] Chi AS, Kim J, Long SS, Morrison WB, Zoga AC. Non-contrast MRI diagnosis of adhesive capsulitis of the shoulder. Clin Imaging. 2017;44:46-50.

[37] Schollmeier G, Uhthoff HK, Sarkar K, Fukuhara K. Effects of immobilization on the capsule of the canine glenohumeral joint. A structural functional study. Clin Orthop Relat Res. 1994;304:37-42.

[38] Uhthoff HK, Boileau P. Primary frozen shoulder: global capsular stiffness versus localized contracture. Clin Orthop Relat Res. 2007;456:79-84.

[39] Pasquali P. The importance of animal models in research. Res Vet Sci. 2018;118:144-145.

[40] Soslowsky LJ, Carpenter JE, DeBano CM, Banerji I, Moalli MR. Development and use of an animal model for investigations on rotator cuff disease. J Shoulder Elb Surg. 1996;5(5):383-392.

[41] Norlin R, Hoe-Hansen C, Oquist G, Hildebrand C. Shoulder region of the rat: anatomy and fiber composition of some suprascapular nerve branches. Anat Rec. 1994;239(3):332-342.

[42] Villa-Camacho JC, Okajima S, Perez-Viloria ME, et al. In vivo kinetic evaluation of an adhesive capsulitis model in rats. J Shoulder Elb Surg. 2015;24(11):1809-1816.

[43] Rauoof MA, Lone NA, Bhat BA, Habib S. Etiological factors and clinical profile of adhesive capsulitis in patients seen at the rheumatology clinic of a tertiary care hospital in India. Saudi Med J. 2004;25(3):359-362.

[44] Liu YL, Ao YF, Cui GQ, Zhu JX. Changes of histology and capsular collagen in a rat shoulder immobilization model. Chin Med J. 2011;124(23):3939-3944.

[45] Colas F, Nevoux J, Gagey O. The subscapular and subcoracoid bursae: descriptive and functional anatomy. J Shoulder Elb Surg. 2004;13(4):454-458.

[46] Kim DH, Lee K-H. Lho Y-M, et al. Characterization of a frozen shoulder model using immobilization in rats. J Orthop Surg Res. 2016;11:160.

[47] Bunker TD, Reilly J, Baird KS, Hamblen DL. Expression of growth factors, cytokines and matrix metalloproteinases in frozen shoulder. J Bone Joint Surg Br. 2000;82(5):768-773.

[48] Kabbabe B, Ramkumar S, Richardson M. Cytogenetic analysis of the pathology of frozen shoulder. Int J Shoulder Surg. 2010;4(3):75-78.

[49] Cho C-H, Lho Y-M, Hwang I, Kim DH. Role of matrix metalloproteinases 2 and 9 in the development of frozen shoulder: human data and experimental analysis in a rat contracture model. J Shoulder Elb Surg. 2019;28(7):1265-1272.

[50] Hutchinson JW, Tierney GM, Parsons SL, Davis TR. Dupuytren’s disease and frozen shoulder induced by treatment with a matrix metalloproteinase inhibitor. J Bone Joint Surg Br. 1998;80(5):907-908.

[51] Taguchi H, Tanaka T, Nishiofuku H, et al. A rat model of Frozen shoulder demonstrating the effect of transcatheter arterial embolization on angiography, histopathology, and physical activity. J Vasc Interv Radiol. 2021;32(3):376-383.

[52] Okuno Y, Iwamoto W, Matsumura N, et al. Clinical outcomes of transcatheter arterial embolization for adhesive capsulitis resistant to conservative treatment. J Vasc Interv Radiol. 2017;28(2):161-167.e161.

[53] Kanno A, Sano H, Itoi E. Development of a shoulder contracture model in rats. J Shoulder Elb Surg. 2010;19(5):700-708.

[54] Yan Y, Zhou M, Meng K, et al. Salvianolic acid B attenuates inflammation and prevent pathologic fibrosis by inhibiting CD36-mediated activation of the PI3K-Akt signaling pathway in frozen shoulder. Front Pharmacol. 2023;14:1230174.

[55] Ahn Y, Moon YS, Park G-Y. et al. Efficacy of intra-articular triamcinolone and hyaluronic acid in a Frozen shoulder rat model. Am J Sports Med. 2023;51(11):2881-2890.

[56] Qiao Y, Yang Y, Wang J, et al. Tuina in a Frozen shoulder rat model: an efficient and reproducible protocol. J Vis Exp. 2023;197:e65440.

[57] Mao X, Li Z, Gu S, et al. MicroRNA-211-5p in extracellular vesicles derived from BMSCs facilitates the repair of rat frozen shoulder via regulating KDM2B/LACC1 axis. Tissue Cell. 2023;81:102006.

[58] Zhang J, Song Y, Zhu L, et al. An injectable thermosensitive hyaluronic acid/pluronic F-127 hydrogel for deep penetration and combination therapy of frozen shoulder. Int J Biol Macromol. 2024;263(Pt 1):130342.

[59] Trudel G, Jabi M, Uhthoff HK. Localized and adaptive synoviocyte proliferation characteristics in rat knee joint contractures secondary to immobility. Arch Phys Med Rehabil. 2003;84(9):1350-1356.

[60] Trudel G, Seki M, Uhthoff HK. Synovial adhesions are more important than pannus proliferation in the pathogenesis of knee joint contracture after immobilization: an experimental investigation in the rat. J Rheumatol. 2000;27(2):351-357.

[61] Bunker TD, Anthony PP. The pathology of frozen shoulder. A Dupuytren-like disease. J Bone Joint Surg Br. 1995;77(5):677-683.

[62] Okajima SM, Cubria MB, Mortensen SJ, et al. Rat model of adhesive capsulitis of the shoulder. J Vis Exp. 2018;139:e58335.

[63] Ochiai N, Ohtori S, Kenmoku T, et al. Sensory innervation of rat contracture shoulder model. J Shoulder Elb Surg. 2013;22(2):158-164.

[64] Ding Q, Xue M, Gong S, Dai J, Chen G, Hu J. The treatment of fibrosis of joint synovium and Frozen shoulder by Smad4 gene silencing in rats. PLoS One. 2016;11(6):e0158093.

[65] Feusi O, Fleischmann T, Waschkies C, Pape H-C, Werner CML, Tiziani S. Vitamin C as a potential prophylactic measure against Frozen shoulder in an in vivo shoulder contracture animal model. Am J Sports Med. 2023;51(8):2041-2049.

[66] Feusi O, Karol A, Fleischmann T, et al. Platelet-rich plasma as a potential prophylactic measure against frozen shoulder in an in vivo shoulder contracture model. Arch Orthop Trauma Surg. 2020;142(3):363-372.

[67] Zhao H, Kong L, Shen J, et al. Tetrandrine inhibits the occurrence and development of frozen shoulder by inhibiting inflammation, angiogenesis, and fibrosis. Biomed Pharmacother. 2021;140:111700.

[68] Cinar BM, Battal VE, Bal N, Guler UO, Beyaz S. Comparison of efficacy of Oral versus intra-articular corticosteroid application in the treatment of Frozen shoulder: an experimental study in rats. Acta Orthop Traumatol Turc. 2022;56(1):64-70.

[69] Chen J, Zhu J, Zhu T, et al. Pathological changes of frozen shoulder in rat model and the therapeutic effect of PPAR-γ agonist. J Orthop Res. 2021;39(4):891-901.

[70] Akbar M, McLean M, Garcia-Melchor E, et al. Fibroblast activation and inflammation in frozen shoulder. PLoS One. 2019;14(4):e0215301.

[71] Leong HT, Fu SC, He X, Oh JH, Yamamoto N, Hang S. Risk factors for rotator cuff tendinopathy: a systematic review and meta-analysis. J Rehabil Med. 2019;51(9):627-637.

[72] Sofka CM, Ciavarra GA, Hannafin JA, Cordasco FA, Potter HG. Magnetic resonance imaging of adhesive capsulitis: correlation with clinical staging. HSS J. 2008;4(2):164-169.

[73] Fields BKK, Skalski MR, Patel DB, et al. Adhesive capsulitis: review of imaging findings, pathophysiology, clinical presentation, and treatment options. Skeletal Radiol. 2019;48(8):1171-1184.

[74] Walmsley S, Rivett DA, Osmotherly PG. Adhesive capsulitis: establishing consensus on clinical identifiers for stage 1 using the DELPHI technique. Phys Ther. 2009;89(9):906-917.

[75] Rundquist PJ, Anderson DD, Guanche CA, Ludewig PM. Shoulder kinematics in subjects with frozen shoulder. Arch Phys Med Rehabil. 2003;84(10):1473-1479.

[76] Shaffer B, Tibone JE, Kerlan RK. Frozen shoulder. A long-term follow-up. J Bone Joint Surg Am. 1992;74(5):738-746.

[77] Patel R, Urits I, Wolf J, et al. A comprehensive update of adhesive capsulitis and minimally invasive treatment options. Psychopharmacol Bull. 2020;50(4 Suppl 1):91-107.

[78] Wu CH, Chen WS, Wang TG. Elasticity of the coracohumeral ligament in patients with adhesive capsulitis of the shoulder. Radiology. 2016;278(2):458-464.

[79] Bunker TD. Time for a new name for ‘frozen shoulder’. Br Med J (Clin Res Ed). 1985;290(6477):1233-1234.

[80] Kilian O, Kriegsmann J, Berghäuser K, Stahl JP, Horas U, Heerdegen R. The frozen shoulder. Arthroscopy, histological findings and transmission electron microscopy imaging. Chirurg. 2001;72(11):1303-1308.

[81] Lewis J. Frozen shoulder contracture syndrome -Aetiology, diagnosis and management. Man Ther. 2015;20(1):2-9.

[82] Itoi E, Arce G, Bain GI, et al. Shoulder stiffness: current concepts and concerns. Art Ther. 2016;32(7):1402-1414.

[83] Cho CH, Lee YH, Kim DH, Lim YJ, Baek CS, Kim DH. Definition, diagnosis, treatment, and prognosis of Frozen shoulder: a consensus survey of shoulder specialists. Clin Orthop Surg. 2020;12(1):60-67.

[84] Shrestha-Taylor S, Clarke JL, Poulos A, Ginn K. Ultrasound features for the diagnosis of adhesive capsulitis/Frozen shoulder: a systematic review. Ultrasound Med Biol. 2022;48(12):2379-2397.

[85] Connell D, Padmanabhan R, Buchbinder R. Adhesive capsulitis: role of MR imaging in differential diagnosis. Eur Radiol. 2002;12(8):2100-2106.

[86] Mengiardi B, Pfirrmann CW, Gerber C, Hodler J, Zanetti M. Frozen shoulder: MR arthrographic findings. Radiology. 2004;233(2):486-492.

[87] Schollmeier G, Sarkar K, Fukuhara K, Uhthoff HK. Structural and functional changes in the canine shoulder after cessation of immobilization. Clin Orthop Relat Res. 1996;323:310-315.

[88] Parks WC, Wilson CL, López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004;4(8):617-629.

[89] Sam N, Yusuf I, Idris I, et al. The level of ratio between matrix metalloproteinase-1 (MMP-1) and tissue inhibitor matrix metalloproteinase-1 (TIMP-1) after prolotherapy intervention and the functional outcome in patient with frozen shoulder: a randomized controlled trial. Medicine (Baltimore). 2023;102(30):e34356.

[90] Chen W, Meng J, Qian H, et al. A study of IL-1β MMP-3, TGF-β1, and GDF5 polymorphisms and their association with primary Frozen shoulder in a Chinese Han population. Biomed Res Int. 2017;2017:3681645.

[91] Lubis AM, Lubis VK. Matrix metalloproteinase, tissue inhibitor of metalloproteinase and transforming growth factor-beta 1 in frozen shoulder, and their changes as response to intensive stretching and supervised neglect exercise. J Orthop Sci. 2013;18(4):519-527.

[92] Liu H, Yu B, Deng Z, et al. Role of immune cell infiltration and small molecule drugs in adhesive capsulitis: novel exploration based on bioinformatics analyses. Front Immunol. 2023;14:1075395.

[93] Lee MJ, Yoon KS, Oh S, Shin S, Jo CH. Allogenic pure platelet-rich plasma therapy for adhesive capsulitis: a bed-to-bench study with propensity score matching using a corticosteroid control group. Am J Sports Med. 2021;49(9):2309-2320.

[94] Kingston K, Curry EJ, Galvin JW, Li X. Shoulder adhesive capsulitis: epidemiology and predictors of surgery. J Shoulder Elb Surg. 2018;27(8):1437-1443.

[95] Dyer BP, Rathod-Mistry T, Burton C, van der Windt D, Bucknall M. Diabetes as a risk factor for the onset of frozen shoulder: a systematic review and meta-analysis. BMJ Open. 2023;13(1):e062377.

[96] Rai SK, Kashid M, Chakrabarty B, Upreti V, Shaki O. Is it necessary to screen patient with adhesive capsulitis of shoulder for diabetes mellitus? J Family Med Prim Care. 2019;8(9):2927-2932.

[97] Zreik NH, Malik RA, Charalambous CP. Adhesive capsulitis of the shoulder and diabetes: a meta-analysis of prevalence. Muscles Ligaments Tendons J. 2016;6(1):26-34.

[98] Gundtoft PH, Attrup ML, Kristensen AK, Vobbe JW, Sørensen L, Hölmich P. Diabetes mellitus affects the prognosis of frozen shoulder. Dan Med J. 2020;67(10):A02200071.

[99] Karbowiak M, Holme T, Mirza M, Siddiqui N. Frozen shoulder. BMJ. 2022;377:e068547.

[100] Yadav H, Jain S, Prasad GB, Yadav M. Preventive effect of diabegon, a polyherbal preparation, during progression of diabetes induced by high-fructose feeding in rats. J Pharmacol Sci. 2007;105(1):12-21.

[101] Redler LH, Dennis ER. Treatment of adhesive capsulitis of the shoulder. J Am Acad Orthop Surg. 2019;27(12):e544-e554.

[102] Ricci M. Adhesive capsulitis: a review for clinicians. Jaapa. 2021;34(12):12-14.

[103] Deng G, Wei Y. The causal relationship between hypothyroidism and frozen shoulder: a two-sample mendelian randomization. Medicine (Baltimore). 2023;102(43):e35650.

[104] Schiefer M, Teixeira PFS, Fontenelle C, et al. Prevalence of hypothyroidism in patients with frozen shoulder. J Shoulder Elb Surg. 2017;26(1):49-55.

[105] Lui PP, Chan LS, Cheuk YC, Lee YW, Chan KM. Expression of bone morphogenetic protein-2 in the chondrogenic and ossifying sites of calcific tendinopathy and traumatic tendon injury rat models. J Orthop Surg Res. 2009;4:27.

[106] Hu C, Ma L, Gao S, et al. PPP1R3A inhibits osteogenesis and negatively regulates intracellular calcium levels in calcific tendinopathy. iScience. 2023;26(10):107784.

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