Skip to main content
Log in

The effects of substance P on tendinopathy are dose-dependent: An in vitro and in vivo model study

  • Published:
The journal of nutrition, health & aging

Abstract

Objectives

Substance P (SP) is known to be involved in neuropathic pain, chronic inflammation, and tendinopathy. The present study evaluated the effects of different doses of SP on tendon-derived stem cells (TDSCs) in vitro and tendons in vivo.

Methods

For the in vitro study, TDSCs cultured in growth medium with different concentrations of SP (negative control, 0.1 nM, and 1.0 nM). The effects of SP on TDSCs were examined with respect to their ability to proliferate and differentiate. For the in vivo study, we injected different doses of SP (saline control, 0.5 nmol, and 5.0 nmol) into rat patella tendons to investigate the effects of SP on tendons.

Results

Low and high doses SP significantly enhanced the proliferation ability of TDSCs. Low-dose of SP induced the expression of tenocyte-related genes; however, high-dose of SP induced the expression of non-tenocyte genes, which was evident by the high expression of PPARγ and collagen type II. In the in vivo study, only high-doses of SP (5.0 nmol) induced the tendinosis-like changes in the patella tendon injection model. Low doses of SP (0.5 nmol) enhanced the tenogenesis compared with saline injection and the high-dose SP group.

Conclusion

SP enhances the proliferation of TDSCs in vitro and the effects of SP on tendinopathy are dose-dependent in vivo..

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, et al. (2007) Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nature medicine 13: 1219–1227.

    Article  CAS  PubMed  Google Scholar 

  2. Rui Y-F, Lui PPY, Li G, Fu SC, Lee YW, et al. (2010) Isolation and characterization of multipotent rat tendon-derived stem cells. Tissue Engineering Part A 16: 1549–1558.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang J, Wang JH (2010) Characterization of differential properties of rabbit tendon stem cells and tenocytes. BMC musculoskeletal disorders 11: 10.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Zhang J, Wang JH (2013) The Effects of Mechanical Loading on Tendons-An In Vivo and In Vitro Model Study. PloS one 8: e717–0.

    Google Scholar 

  5. Rui YF, Lui PPY, Wong YM, Tan Q, Chan KM (2013) BMP-2 stimulated nontenogenic differentiation and promoted proteoglycan deposition of tendon-derived stem cells (TDSCs) in vitro. Journal of Orthopaedic Research 31: 746–753.

    Article  CAS  PubMed  Google Scholar 

  6. Zhou B, Zhou Y, Tang K (2014) An overview of structure, mechanical properties, and treatment for age-related tendinopathy. The journal of nutrition, health & aging 18: 441–448.

    Article  CAS  Google Scholar 

  7. Schubert T, Weidler C, Borisch N, Schubert C, Hofstädter F, et al. (2006) Dupuytren’s contracture is associated with sprouting of substance P positive nerve fibres and infiltration by mast cells. Annals of the rheumatic diseases 65: 414–415.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Ziche M, Morbidelli L, Masini E, Amerini S, Granger H, et al. (1994) Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. Journal of Clinical Investigation 94: 20–6.

    Article  Google Scholar 

  9. Fearon AM, Twin J, Dahlstrom JE, Cook JL, Cormick W, et al. (2014) Increased substance P expression in the trochanteric bursa of patients with greater trochanteric pain syndrome. Rheumatology international: 1–8.

    Google Scholar 

  10. Gotoh M, Hamada K, Yamakawa H, Inoue A, Fukuda H (1998) Increased substance P in subacromial bursa and shoulder pain in rotator cuff diseases. Journal of orthopaedic research 16: 618–621.

    Article  CAS  PubMed  Google Scholar 

  11. Walsh D, Mapp PI, Wharton J, Rutherford R, Kidd B, et al. (1992) Localisation and characterisation of substance P binding to human synovial tissue in rheumatoid arthritis. Annals of the rheumatic diseases 51: 313–317.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Andersson G, Danielson P, Alfredson H, Forsgren S (2008) Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon. Regulatory peptides 150: 81–87.

    Article  CAS  PubMed  Google Scholar 

  13. Zhou B, Zhou Y, Tang K (2014) The effects of substance P on pluripotent tendon cells: an in vitro and in vivo study. J Musculoskelet Neuronal Interact 14: 349–358.

    CAS  PubMed  Google Scholar 

  14. Schubert T, Weidler C, Lerch K, Hofstädter F, Straub R (2005) Achilles tendinosis is associated with sprouting of substance P positive nerve fibres. Annals of the rheumatic diseases 64: 1083–1086.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Öztürk N, Erin N, Tüzüner S (2010) Changes in tissue substance P levels in patients with carpal tunnel syndrome. Neurosurgery 67: 1655–1661.

    Article  PubMed  Google Scholar 

  16. Andersson G, Backman LJ, Scott A, Lorentzon R, Forsgren S, et al. (2011) Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model. British journal of sports medicine 45: 1017–1022.

    Article  PubMed  Google Scholar 

  17. Carlsson O, Schizas N, Li J, Ackermann P (2011) Substance P injections enhance tissue proliferation and regulate sensory nerve ingrowth in rat tendon repair. Scandinavian journal of medicine & science in sports 21: 562–569.

    Article  CAS  Google Scholar 

  18. Steyaert A, Burssens P, Forsyth R, Vanderstraeten G (2010) Qualitative analysis of substance P, NK1-receptor and nerve ingrowth in substance P-treated ruptured rat Achilles tendon. Acta Orthopædica Belgica 76: 3–7.

    Google Scholar 

  19. Backman LJ, Fong G, Andersson G, Scott A, Danielson P (2011) Substance P is a mechanoresponsive, autocrine regulator of human tenocyte proliferation. PloS one 6: e272–9.

    Article  Google Scholar 

  20. Chen L, Dong S, Tao X, Liu J, Tang K, et al. (2012) Autologous platelet-rich clot releasate stimulates proliferation and inhibits differentiation of adult rat tendon stem cells towards nontenocyte lineages. Journal of International Medical Research 40: 1399–1409.

    Article  CAS  PubMed  Google Scholar 

  21. Liu J, Chen L, Tao X, Tang K (2013) Phosphoinositide 3-kinase/Akt signaling is essential for prostaglandin E2-induced osteogenic differentiation of rat tendon stem cells. Biochemical and biophysical research communications 435: 514–519.

    Article  CAS  PubMed  Google Scholar 

  22. Liu J, Chen L, Liu X, Tang K (2014) Insulin-Like Growth Factor-1 and Bone Morphogenetic Protein-2 Jointly Mediate Prostaglandin E2-Induced Adipogenic Differentiation of Rat Tendon Stem Cells. PloS one 9: e854–9.

    Google Scholar 

  23. Zhang J, Wang JHC (2010) Mechanobiological response of tendon stem cells: implications of tendon homeostasis and pathogenesis of tendinopathy. Journal of Orthopaedic Research 28: 639–643.

    Article  PubMed  Google Scholar 

  24. Franceschi F, Longo UG, Ruzzini L, Morini S, Battistoni F, et al. (2008) Circulating substance P levels and shoulder joint contracture after arthroscopic repair of the rotator cuff. British Journal of Sports Medicine 42: 742–745.

    Article  CAS  PubMed  Google Scholar 

  25. Andersson G, Danielson P, Alfredson H, Forsgren S (2007) Nerve-related characteristics of ventral paratendinous tissue in chronic Achilles tendinosis. Knee Surgery, Sports Traumatology, Arthroscopy 15: 1272–1279.

    Article  PubMed  Google Scholar 

  26. Harrison S, Geppetti P (2001) Substance p. The international journal of biochemistry & cell biology 33: 555–576.

    Article  CAS  Google Scholar 

  27. Andersson G, Forsgren S, Scott A, Gaida JE, Stjernfeldt JE, et al. (2011) Tenocyte hypercellularity and vascular proliferation in a rabbit model of tendinopathy: contralateral effects suggest the involvement of central neuronal mechanisms. British journal of sports medicine 45: 399–406.

    Article  PubMed  Google Scholar 

  28. Ackermann PW, Ahmed M, Kreicbergs A (2002) Early nerve regeneration after Achilles tendon rupture—a prerequisite for healing? A study in the rat. Journal of orthopaedic research 20: 849–856.

    Article  Google Scholar 

  29. Fong G, Backman LJ, Hart DA, Danielson P, McCormack B, et al. (2013) Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes. Journal of Orthopaedic Research 31: 91–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Bring DKI, Heidgren ML, Kreicbergs A, Ackermann PW (2005) Increase in sensory neuropeptides surrounding the Achilles tendon in rats with adjuvant arthritis. Journal of orthopaedic research 23: 294–301.

    Article  CAS  PubMed  Google Scholar 

  31. Backman L, Andersson G, Wennstig G, Forsgren S, Danielson P (2011) Endogenous substance P production in the Achilles tendon increases with loading in an in vivo model of tendinopathy-peptidergic elevation preceding tendinosis-like tissue changes. J Musculoskelet Neuronal Interact 11: 133–140.

    CAS  PubMed  Google Scholar 

  32. Sato Y, Itoh H, Suzuki Y, Tatsuta R, Takeyama M (2013) Effect of pilocarpine on substance P and calcitonin gene-related peptide releases correlate with salivary secretion in human saliva and plasma. Journal of clinical pharmacy and therapeutics 38: 19–23.

    Article  CAS  PubMed  Google Scholar 

  33. Lui PP-Y, Chan L-s, Fu S-c, Chan K-m (2010) Expression of sensory neuropeptides in tendon is associated with failed healing and activity-related tendon pain in collagenase-induced tendon injury. The American journal of sports medicine 38: 757–764.

    Article  PubMed  Google Scholar 

  34. Song Y, Stål PS, Yu J-G, Lorentzon R, Backman C, et al. (2014) Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model. BMC musculoskeletal disorders 15: 1–6.

    Article  Google Scholar 

  35. Lam F, Ferrell W (1989) Inhibition of carrageenan induced inflammation in the rat knee joint by substance P antagonist. Annals of the rheumatic diseases 48: 928–932.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Bring DKI, Paulson K, Renstrom P, Salo P, Hart DA, et al. (2012) Residual substance P levels after capsaicin treatment correlate with tendon repair. Wound Repair and Regeneration 20: 50–60.

    Article  PubMed  Google Scholar 

  37. Khan KM, Cook JL, Bonar F, Harcourt P, Åstrom M (1999) Histopathology of common tendinopathies. Sports Medicine 27: 393–408.

    Google Scholar 

  38. Backman LJ, Danielson P (2013) Akt-mediated anti-apoptotic effects of substance P in Anti-Fas-induced apoptosis of human tenocytes. Journal of cellular and molecular medicine.

    Google Scholar 

  39. Fedorczyk JM, Barr AE, Rani S, Gao HG, Amin M, et al. (2010) Exposuredependent increases in IL-1ß, substance P, CTGF, and tendinosis in flexor digitorum tendons with upper extremity repetitive strain injury. Journal of Orthopaedic Research 28: 298–307.

    PubMed Central  PubMed  Google Scholar 

  40. Backman LJ, Eriksson DE, Danielson P (2013) Substance P reduces TNF-a-induced apoptosis in human tenocytes through NK-1 receptor stimulation. British journal of sports medicine: bjsports-2013-0924-8.

    Google Scholar 

  41. Terenzi R, Romano E, Manetti M, Peruzzi F, Nacci F, et al. (2013) Neuropeptides activate TRPV1 in rheumatoid arthritis fibroblast-like synoviocytes and foster IL-6 and IL-8 production. Annals of the rheumatic diseases 72: 1107–1109.

    Article  CAS  PubMed  Google Scholar 

  42. Ljung BO, Alfredson H, Forsgren S (2004) Neurokinin 1-receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus Studies on tennis elbow and medial epicondylalgia. Journal of orthopaedic research 22: 321–327.

    Article  CAS  PubMed  Google Scholar 

  43. Zhang J, Wang JH (2014) Prostaglandin E2 (PGE2) Exerts Biphasic Effects on Human Tendon Stem Cells. PloS one 9: e877–6.

    Google Scholar 

  44. Garrett N, Mapp P, Cruwys S, Kidd B, Blake D (1992) Role of substance P in inflammatory arthritis. Annals of the rheumatic diseases 51: 1014–1018.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kanglai Tang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, Y., Zhou, B. & Tang, K. The effects of substance P on tendinopathy are dose-dependent: An in vitro and in vivo model study. J Nutr Health Aging 19, 555–561 (2015). https://doi.org/10.1007/s12603-014-0576-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12603-014-0576-3

Keywords

Navigation