Abstract
Cigarette smoking is the largest cause of preventable deaths, and a known risk factor for musculoskeletal issues including rotator cuff tendon tears. Tendon degeneration is believed to be due in part to changes in tendon cell health and collagen structure. Several studies have demonstrated that exposure to nicotine negatively impacts tendon healing, but surprisingly, nicotine exposure was shown to increase rat supraspinatus tendon stiffness. In order to address this seeming contradiction, the objective of this study was to comprehensively investigate the effects of long-term (18 weeks) exposure of nicotine on tendon-to-bone microstructural properties in a rat model. We hypothesized that long term subcutaneous nicotine delivery would lead to diminished tendon mechanical properties, decreased bone microstructure in the humeral head, and altered tendon cell morphology compared to age-matched control rats receiving saline. Results demonstrated a small decrease in tendon size and stiffness, with decreased cell density in the tendon midsubstance. However, no differences were found in the enthesis fibrocartilage or in the underlying subchondral or trabecular bone. In conclusion, our study revealed limited effects of nicotine on the homeostatic condition of the supraspinatus tendon, enthesis, and underlying bone. Future studies are needed to ascertain effects of other components of tobacco products.
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References
Akhter, M. P., U. T. Iwaniec, G. R. Haynatzki, Y. K. Fung, D. M. Cullen, and R. R. Recker. Effects of nicotine on bone mass and strength in aged female rats. J. Orthop. Res. 21:14–19, 2003.
Apostolakos, J., T. J. Durant, C. R. Dwyer, R. P. Russell, J. H. Weinreb, F. Alaee, K. Beitzel, M. B. McCarthy, M. P. Cote, and A. D. Mazzocca. The enthesis: a review of the tendon-to-bone insertion. Muscles Ligaments Tendons J. 4:333–342, 2014.
Benson, B. W., and J. D. Shulman. Inclusion of tobacco exposure as a predictive factor for decreased bone mineral content. Nicotine Tob. Res. 7:719–724, 2005.
Berman, D., J. H. Oren, J. Bendo, and J. Spivak. The effect of smoking on spinal fusion. Int. J. Spine Surg. 11:29, 2017.
Biondo-Simões, M. L., N. W. Spelling, S. I. Ioshii, R. Biondo-Simões, and J. C. Repka. The influence of nicotine on the population of fibroblasts in cutaneous scars in rats. Acta Circ. Bras. 24:466–470, 2009.
Bishop, J. Y., J. E. Santiago-Torres, N. Rimmke, and D. C. Flanigan. Smoking predisposes to rotator cuff pathology and shoulder dysfunction: a systematic review. Arthroscopy. 31:1598–1605, 2015.
Blackford, A. L., G. Yang, M. Hernandez-Avila, K. Przewozniak, W. Zatonski, V. Figueiredo, E. Avila-Tang, J. Ma, N. L. Benowitz, and J. M. Samet. Cotinine concentration in smokers from different countries: relationship with amount smoked and cigarette type. Cancer Epidemiol. Biomark. Prev. 15:1799–1804, 2006.
Bonilla, K. A., A. M. Pardes, B. R. Freedman, and L. J. Soslowsky. Supraspinatus tendons have different mechanical properties across sex. J. Biomech. Eng. 141:011002, 2019.
Broulik, P. D., J. Rosenkrancová, P. Růzicka, R. Sedlácek, and I. Kurcová. The effect of chronic nicotine administration on bone mineral content and bone strength in normal and castrated male rats. Horm. Metab. Res. 39:20–24, 2007.
Cheema, A. N., J. B. Newton, J. F. Boorman-Padgett, S. N. Weiss, C. A. Nuss, D. J. Gittings, D. C. Farber, and L. J. Soslowsky. Nicotine impairs intra-substance tendon healing after full thickness injury in a rat model. J. Orthop. Res. 37:94–103, 2019.
Chen, X., H. Giambini, E. Ben-Abraham, K. N. An, A. Nassr, and C. Zhao. Effect of bone mineral density on rotator cuff tear: an osteoporotic rabbit model. PLoS ONE. 10:e0139384, 2015.
Cusano, N. E. Skeletal effects of smoking. Curr. Osteoporos. Rep. 13:302–309, 2015.
Daffner, S. D., S. Waugh, T. L. Norman, N. Mukherjee, and J. C. France. Nicotine increases osteoblast activity of induced bone marrow stromal cells in a dose-dependent manner: an in vitro cell culture experiment. Global Spine J. 2:153–158, 2012.
Favata, M. Scarless healing in the fetus: implications and strategies for postnatal tendon repair [PhD thesis]. Philadelphia: University of Pennsylvania, 2006.
France, J. C., T. L. Norman, M. M. Buchanan, M. Scheel, M. Veale, E. S. Ackerman, N. B. Clovis, V. L. Kish, and B. Simon. Direct current stimulation for spine fusion in a nicotine exposure model. Spine J. 6:7–13, 2006.
Fung, A.K., S.S. Shetye, Y. Li, X.S. Liu, and L.J. Soslowsky. Pregnancy and lactation impair subchondral bone leading to reduced rat supraspinatus tendon failure [published online ahead of print, 2020 Jun 25]. J. Biomech. Eng., 2020.
Galatz, L. M., M. J. Silva, S. Y. Rothermich, M. A. Zaegel, N. Havlioglu, and S. Thomopoulos. Nicotine delays tendon-to-bone healing in a rat shoulder model. J. Bone Joint Surg. Am. 88:2027–2034, 2006.
Gimbel, J. A., J. P. Van Kleunen, S. Mehta, S. M. Perry, G. R. Williams, and L. J. Soslowsky. Supraspinatus tendon organizational and mechanical properties in a chronic rotator cuff tear animal model. J. Biomech. 37:739–749, 2004.
Gittings, D., C. Riggin, J. Boorman-Padgett, S. Weiss, G. Fryhofer, D. Farber, D. Steinberg, and L. J. Soslowsky. Chronic nicotine exposure alters uninjured tendon vascularity and viscoelasticity. Foot Ankle Orthopaed. 4:1–7, 2019.
Gullahorn, L., L. Lippiello, and R. Karpman. Smoking and osteoarthritis: differential effect of nicotine on human chondrocyte glycosaminoglycan and collagen synthesis. Osteoarthr. Cartil. 13:942–943, 2005.
Hu, T., H. Y. Sung, T. E. Keeler, and M. Marciniak. Cigarette consumption and sales of nicotine replacement products. Tob. Control 9:60–63, 2000.
Huegel, J., D. S. Choi, C. A. Nuss, M. C. C. Minnig, J. J. Tucker, A. F. Kuntz, E. I. Waldorff, N. Zhang, J. T. Ryaby, and L. J. Soslowsky. Effects of pulsed electromagnetic field therapy at different frequencies and durations on rotator cuff tendon-to-bone healing in a rat model. J. Shoulder Elbow Surg. 27:553–560, 2018.
Ichinose, R., H. Sano, K. N. Kishimoto, N. Sakamoto, M. Sato, and E. Itoi. Alteration of the material properties of the normal supraspinatus tendon by nicotine treatment in a rat model. Acta Orthop. 81:634–638, 2010.
Iwaniec, U. T., G. R. Haynatzki, Y. K. Fung, M. P. Akhter, M. C. Haven, and D. M. Cullen. Effects of nicotine on bone and calciotropic hormones in aged ovariectomized rats. J. Musculoskelet. Neuronal Interact. 2:469–478, 2002.
Jiang, Y., J. Zhao, M. T. van Holsbeeck, M. J. Flynn, X. Ouyang, and H. K. Genant. Trabecular microstructure and surface changes in the greater tuberosity in rotator cuff tears. Skelet. Radiol. 31:522–528, 2002.
Lujan, T. J., C. J. Underwood, N. T. Jacobs, and J. A. Weiss. Contribution of glycosaminoglycans to viscoelastic tensile behavior of human ligament. J. Appl. Physiol. 106(423–431):2009, 1985.
Pardes, A. M., B. R. Freedman, G. W. Fryhofer, N. S. Salka, P. R. Bhatt, and L. J. Soslowsky. Males have inferior Achilles tendon material properties compared to females in a rodent model. Ann. Biomed. Eng. 44:2901–2910, 2016.
Screen, H. R., S. Toorani, and J. C. Shelton. Microstructural stress relaxation mechanics in functionally different tendons. Med. Eng. Phys. 35:96–102, 2013.
Sengupta, P. The Laboratory Rat: Relating Its Age With Human’s. Int. J. Prev. Med. 4:624–630, 2013.
Skott, M., T. T. Andreassen, M. Ulrich-Vinther, X. Chen, D. E. Keyler, M. G. LeSage, P. R. Pentel, J. E. Bechtold, and K. Soballe. Tobacco extract but not nicotine impairs the mechanical strength of fracture healing in rats. J. Orthop Res. 24:1472–1479, 2006.
St. Charles, F. K., G. R. Krautter, M. Dixon, and D. C. Mariner. A comparison of nicotine dose estimates in smokers between filter analysis, salivary cotinine, and urinary excretion of nicotine metabolites. Psychopharmacology (Berl.) 189:345–354, 2006.
Acknowledgments
Funding provided by the Orthopaedic Research and Education Foundation Grant (#17-011) and the NIH/NIAMS supported Penn Center for Musculoskeletal Disorders (P30 AR069619). We thank Ashley Fung for help with μCT assays.
Funding
Funding provided by the Orthopaedic Research and Education Foundation Grant (#17-011) and NIH/NIAMS supported Penn Center for Musculoskeletal Disorders Grant (5P30AR069619).
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JH contributed to research design, data acquisition, analysis, interpretation, and drafting and editing the manuscript. CAN and PYWC contributed to data acquisition, analysis, and critical review of the manuscript. ANC contributed to research design, animal procedures, and critical review of the manuscript. AFK and LJS contributed to research design, interpretation, and critical review of the manuscript. All authors have read and approved the final manuscript for submission.
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Supplemental Fig. 1. Representative full-length histology images with H&E stain (left) and Safranin-O stain (right) indicating regions of interest for mechanical properties (left) and histological assessments (right). Supplementary material 1 (PNG 893 kb)
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Supplemental Fig. 2. Representative loading curve (top) and corresponding tendon extension (bottom) demonstrate data from which viscoelastic (i.e. tendon stiffness) and quasi-static (stress relaxation) properties were calculated. The loading curve is labeled with specific elements of the test protocol including a pre-conditioning, b stress relaxation, and c ramp to failure. Supplementary material 2 (PNG 91 kb)
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Huegel, J., Nuss, C.A., Chan, P.Y.W. et al. Chronic Nicotine Exposure Minimally Affects Rat Supraspinatus Tendon Properties and Bone Microstructure. Ann Biomed Eng 49, 1333–1341 (2021). https://doi.org/10.1007/s10439-020-02667-x
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DOI: https://doi.org/10.1007/s10439-020-02667-x