Expression of sensory neuropeptides in tendon is associated with failed healing and activity-related tendon pain in collagenase-induced tendon injury

Am J Sports Med. 2010 Apr;38(4):757-64. doi: 10.1177/0363546509355402. Epub 2010 Feb 5.


Background: Increase in expression of substance P (SP) and calcitonin gene-related peptide (CGRP) has been reported in clinical samples of tendinopathy.

Purpose: To examine the spatial-temporal expression of these neuropeptides as well as their association with activity-related tendon pain, matrix degeneration, failed healing, and pathologic calcification in an established collagenase-induced tendon injury rat model.

Study design: Controlled laboratory study.

Methods: Collagenase or saline was injected into the patellar tendon of rats. At weeks 2, 4, 8, 12, and 16, just before the rats were sacrificed, the double-stance duration of rats was examined by gait analysis method. After sacrifice, the patellar tendons were harvested for histologic analysis and immunohistochemical staining of SP and CGRP.

Results: There was an increase of SP and CGRP immunopositivity in tendon fibroblasts at week 2. The immunopositive signals decreased at weeks 4 and 8 and were observed in chondrocyte-like cells. At weeks 12 and 16, the immunopositive staining increased again and was observed in cells embedded in calcific deposits in addition to tendon fibroblasts and chondrocyte-like cells. The expression pattern was consistent with matrix degeneration, calcification, and failed healing in the animal model. There were significant positive correlations of immunopositivity of SP (rho = .502, P = .002) and CGRP (rho = .483, P = .003) with double-stance duration after collagenase injection.

Conclusion: There was increased expression of SP and CGRP after collagenase-induced tendon injury, and their expression was positively associated with double-stance duration. Clinical Relevance Substance P and CGRP might be involved in the pathogenesis and origin of pain of tendinopathy and could be the targets for future intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcinosis / metabolism
  • Calcinosis / pathology
  • Calcitonin Gene-Related Peptide / analysis
  • Calcitonin Gene-Related Peptide / biosynthesis*
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Collagenases / pharmacology
  • Gait / physiology
  • Male
  • Pain / etiology
  • Pain / metabolism*
  • Patellar Ligament / drug effects
  • Patellar Ligament / injuries*
  • Patellar Ligament / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Substance P / analysis
  • Substance P / biosynthesis*
  • Tendinopathy / complications
  • Tendinopathy / metabolism*
  • Tendinopathy / pathology
  • Wound Healing*


  • Substance P
  • Collagenases
  • Calcitonin Gene-Related Peptide