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Rebalancing SMAD7/SMAD3 Signaling Reduces Adhesion Formation during Flexor Tendon Healing

  • Ke Jiang (Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College) ;
  • Yuling Li (Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College) ;
  • Chao Xiang (Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College) ;
  • Yan Xiong (Department of Orthopaedics, Daping Hospital, Army Medical University) ;
  • Jiameng Jia (Department of Rehabilitation, Affiliated Hospital of North Sichuan Medical College)
  • Received : 2022.09.21
  • Accepted : 2023.02.08
  • Published : 2023.03.28

Abstract

Transforming growth factor-β is a key factor in regulating adhesion formation during tendon healing. We investigated the effectiveness of SMAD family members, SMAD7 and SMAD3, in the TGF-β/Smad signaling during flexor tendon repair. Mouse flexor toe deep tendon rupture anastomosis models were made. On days 3, 7, 14, 21, and 28, the expressions of smad7 and smad3 in flexor tendon tissues were detected by RT-qPCR and western blot. Furthermore, postoperative intraperitoneal injections of SMAD7 agonists or SMAD3 antagonists were given. The degree of tendon healing was evaluated by adhesion testing and biomechanical experiments. Hematoxylin and eosin (HE) staining was used to observe the pathological changes. Immunohistochemistry was used to evaluate the expressions of collagen III, SMAD3, and SMAD7. The mRNA levels of matrix metalloproteinases, Mmp2 and Mmp9, and scleraxis (SCX) in flexor tendon tissue were detected by RT-qPCR. Smad3 expression increased and Smad7 expression decreased in flexor tendon tissue after injury. In addition, the SMAD7 agonist blocked SMAD3 phosphorylation. SMAD7 agonist and SMAD3 antagonist both improved adhesion formation during flexor tendon healing, and decreased the expressions of collagen III, Mmp9, and SCX, while increasing Mmp2 expression. This study provides a possible theoretical basis for the SMAD7-SMAD3 signal cascade during flexor tendon adhesion healing.

Keywords

Acknowledgement

This study was supported by the Ministry of Education (Grant No.: KLET-202013); the Key Laboratory of Emergency and Trauma (Hainan Medical University) Ministry of Education (grant nos. KLET-202013)and the National Nature Science Foundation of China (Grant No.: 81772330).

References

  1. Tang JB. 2005. Clinical outcomes associated with flexor tendon repair. Hand Clin. 21: 199-210. https://doi.org/10.1016/j.hcl.2004.11.005
  2. Karakaplan M, Kilinc O, Ceylan MF, Ertem K, Aslanturk O. 2021. Mid-term results of two-stage tendon reconstruction of zone II flexor tendon injuries. Niger. J. Clin. Pract. 24: 1174-1180. https://doi.org/10.4103/njcp.njcp_249_20
  3. Peters SE, Jha B, Ross M. 2021. Rehabilitation following surgery for flexor tendon injuries of the hand. Cochrane Database Syst. Rev. 1: Cd012479.
  4. Liu C, Yu K, Bai J, Tian D. 2018. Experimental study of tendon sheath repair via decellularized amnion to prevent tendon adhesion. PLoS One 13: e0205811.
  5. Kvist M, Jozsa L, Jarvinen MJ, Kvist H. 1987. Chronic Achilles paratenonitis in athletes: a histological and histochemical study. Pathology 19: 1-11. https://doi.org/10.3109/00313028709065127
  6. Mailey B, O'Shea G, Romanelli M, West B. 2021. Systemic immunosuppression for prevention of recurrent tendon adhesions. Plast. Reconstr. Surg. Glob. Open 9: e3834.
  7. Harrison R, Mudera V, Grobbelaar A, Jones M, McGrouther D. 2003. Synovial sheath cell migratory response to flexor tendon injury: an experimental study in rats. J. Hand Surg. Am. 28: 987-993. https://doi.org/10.1016/S0363-5023(03)00380-0
  8. Maggi R, Maggi C. 2002. Tendon surgery in Brown's syndrome. J. Pediatr. Ophthalmol. Strabismus 39: 33-38. https://doi.org/10.3928/0191-3913-20020101-08
  9. Rowlands DS, Shultz SP, Ogawa T, Aoi W, Korte M. 2014. The effects of uniquely-processed titanium on biological systems: implications for human health and performance. J. Funct. Biomater. 5: 1-14. https://doi.org/10.3390/jfb5010001
  10. Wu LM, Wang JK, Liu J, Fan CC, Wang YJ, Xiong Y. 2021. Gait analysis combined with the expression of TGF-β1, TGF-β3, and CREB during Achilles tendon healing in rat. Chin. J. Traumatol. 24: 360-367. https://doi.org/10.1016/j.cjtee.2021.10.002
  11. Wang D, Pun CCM, Huang S, Tang TCM, Ho KKW, Rothrauff BB, et al. 2020. Tendon-derived extracellular matrix induces mesenchymal stem cell tenogenesis via an integrin/transforming growth factor-β crosstalk-mediated mechanism. FASEB J. 34: 8172-8186. https://doi.org/10.1096/fj.201902377RR
  12. Wu C, Jiang J, Boye A, Jiang Y, Yang Y. 2014. Compound Astragalus and Salvia miltiorrhiza extract suppresses rabbits' hypertrophic scar by modulating the TGF-β/Smad signal. Dermatology 229: 363-368. https://doi.org/10.1159/000365784
  13. Zhang K, Fang T, Shao Y, Wu Y. 2021. TGF-β-MTA1-SMAD7-SMAD3-SOX4-EZH2 signaling axis promotes viability, migration, invasion and EMT of hepatocellular carcinoma cells. Cancer Manag. Res. 13: 7087-7099. https://doi.org/10.2147/CMAR.S297765
  14. Yang Q, Chen HY, Wang JN, Han HQ, Jiang L, Wu WF, et al. 2020. Alcohol promotes renal fibrosis by activating Nox2/4-mediated DNA methylation of Smad7. Clin. Sci. 134: 103-122. https://doi.org/10.1042/CS20191047
  15. Nagar H, Kim S, Lee I, Kim S, Choi SJ, Piao S, et al. 2021. Downregulation of CR6-interacting factor 1 suppresses keloid fibroblast growth via the TGF-β/Smad signaling pathway. Sci. Rep. 11: 500.
  16. Flanders KC, Major CD, Arabshahi A, Aburime EE, Okada MH, Fujii M, et al. 2003. Interference with transforming growth factor-beta/ Smad3 signaling results in accelerated healing of wounds in previously irradiated skin. Am. J. Pathol. 163: 2247-2257. https://doi.org/10.1016/S0002-9440(10)63582-1
  17. Zhong C, Zhang YF, Huang JH, Wang ZY, Chen QY, Su LT, et al. 2017. The Chinese medicine, Jianpi Huayu Decoction, inhibits the epithelial mesenchymal transition via the regulation of the Smad3/Smad7 cascade. Am. J. Transl. Res. 9: 2694-2711.
  18. Jiang K, Chun G, Wang Z, Du Q, Wang A, Xiong Y. 2016. Effect of transforming growth factor-β3 on the expression of Smad3 and Smad7 in tenocytes. Mol. Med. Rep. 13: 3567-3573. https://doi.org/10.3892/mmr.2016.4944
  19. Loiselle AE, Bragdon GA, Jacobson JA, Hasslund S, Cortes ZE, Schwarz EM, et al. 2009. Remodeling of murine intrasynovial tendon adhesions following injury: MMP and neotendon gene expression. J. Orthop. Res. 27: 833-840. https://doi.org/10.1002/jor.20769
  20. Jiang K, Li Y, Xiang C, Xiong Y, Jia J. 2021. TGF-β3 regulates adhesion formation through the JNK/c-Jun pathway during flexor tendon healing. BMC Musculoskelet. Disord. 22: 843.
  21. Loiselle AE, Frisch BJ, Wolenski M, Jacobson JA, Calvi LM, Schwarz EM, et al. 2012. Bone marrow-derived matrix metalloproteinase-9 is associated with fibrous adhesion formation after murine flexor tendon injury. PLoS One 7: e40602.
  22. Hasslund S, Jacobson JA, Dadali T, Basile P, Ulrich-Vinther M, Soballe K, et al. 2008. Adhesions in a murine flexor tendon graft model: autograft versus allograft reconstruction. J. Orthop. Res. 26: 824-833. https://doi.org/10.1002/jor.20531
  23. 2010. Adhesions in a murine flexor tendon graft model: Autograft versus allograft reconstruction. J. Orthop. Res. 26: 824-833. https://doi.org/10.1002/jor.20531
  24. Loiselle A, Bragdon G, Jacobson J, Hasslund S, Cortes Z, Schwarz E, et al. 2009. Remodeling of murine intrasynovial tendon adhesions following injury: MMP and neotendon gene expression. J. Orthop. Res. 27: 833-840. https://doi.org/10.1002/jor.20769
  25. Ackerman JE, Best KT, O'Keefe RJ, Loiselle AE. 2017. Deletion of EP4 in S100a4-lineage cells reduces scar tissue formation during early but not later stages of tendon healing. Sci. Rep. 7: 8658.
  26. Jelinsky SA, Li L, Ellis D, Archambault J, Li J, St Andre M, et al. 2011. Treatment with rhBMP12 or rhBMP13 increase the rate and the quality of rat Achilles tendon repair. J. Orthop. Res. 29: 1604-1612. https://doi.org/10.1002/jor.21427
  27. Kerwin L, El Tal A, Stiff M, Fakhouri T. 2014. Scar prevention and remodeling: a review of the medical, surgical, topical and light treatment approaches. Int. J. Dermatol. 53: 922-936. https://doi.org/10.1111/ijd.12436
  28. Loiselle A, Yukata K, Geary M, Kondabolu S, Shi S, Jonason J, et al. 2015. Development of antisense oligonucleotide (ASO) technology against Tgf-β signaling to prevent scarring during flexor tendon repair. J. Orthop. Res. 33: 859-866. https://doi.org/10.1002/jor.22890
  29. Derynck R, Zhang Y. 2003. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425: 577-584. https://doi.org/10.1038/nature02006
  30. Moustakas A, Souchelnytskyi S, Heldin C. 2001. Smad regulation in TGF-beta signal transduction. J. Cell Sci. 114: 4359-4369. https://doi.org/10.1242/jcs.114.24.4359
  31. Beredjiklian P. 2003. Biologic aspects of flexor tendon laceration and repair. J. Bone Joint Surg. Am. 85: 539-550. https://doi.org/10.2106/00004623-200303000-00025
  32. Bates S, Morrow E, Zhang A, Pham H, Longaker M, Chang J. 2006. Mannose-6-phosphate, an inhibitor of transforming growth factor-beta, improves range of motion after flexor tendon repair. J. Bone Joint Surg. Am. 88: 2465-2472.
  33. Chang J, Thunder R, Most D, Longaker M, Lineaweaver W. 2000. Studies in flexor tendon wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion. Plast. Reconstr. Surg. 105: 148-155. https://doi.org/10.1097/00006534-200001000-00025
  34. Katzel E, Wolenski M, Loiselle A, Basile P, Flick L, Langstein H, et al. 2011. Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing. J. Orthop. Res. 29: 684-693. https://doi.org/10.1002/jor.21235
  35. Murchison ND, Price BA, Conner DA, Keene DR, Olson EN, Tabin CJ, et al. 2007. Regulation of tendon differentiation by scleraxis distinguishes force-transmitting tendons from muscle-anchoring tendons. Development 134: 2697-2708. https://doi.org/10.1242/dev.001933
  36. Sakabe T, Sakai K, Maeda T, Sunaga A, Furuta N, Schweitzer R, et al. 2018. Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice. J. Biol. Chem. 293: 5766-5780. https://doi.org/10.1074/jbc.RA118.001987
  37. Wang X, Chen H, Liu W, Liu M, Zhou D, Chen Q, et al. 2020. The association of plasma high-density lipoprotein cholesterol levels and cirrhosis development in obese patients with chronic hepatitis B: a cohort study. Eur. J. Gastroenterol. Hepatol. 33: 738-744. https://doi.org/10.1097/MEG.0000000000001965
  38. Lorda-Diez C, Montero J, Martinez-Cue C, Garcia-Porrero J, Hurle JJTJobc. 2009. Transforming growth factors beta coordinate cartilage and tendon differentiation in the developing limb mesenchyme. J. Biol. Chem. 284: 29988-29996. https://doi.org/10.1074/jbc.M109.014811
  39. Ding B, Wang X. 2019. Photochemical tissue bonding technique for improving healing of hand tendon injury. Surg. Innov. 26: 153-161. https://doi.org/10.1177/1553350618824448
  40. Oshiro W, Lou J, Xing X, Tu Y, Manske P. 2003. Flexor tendon healing in the rat: a histologic and gene expression study. J. Hand Surg. 28: 814-823. https://doi.org/10.1016/S0363-5023(03)00366-6
  41. Islam SS, Mokhtari RB, El Hout Y, Azadi MA, Alauddin M, Yeger H, et al. 2014. TGF-β1 induces EMT reprogramming of porcine bladder urothelial cells into collagen producing fibroblasts-like cells in a Smad2/Smad3-dependent manner. J. Cell Commun. Signal. 8: 39-58. https://doi.org/10.1007/s12079-013-0216-4
  42. Bramono D, Richmond J, Weitzel P, Kaplan D, Altman G. 2004. Matrix metalloproteinases and their clinical applications in orthopaedics. Clin. Orthop. Relat. Res. 428: 272-285. https://doi.org/10.1097/01.blo.0000144166.66737.3a