Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes

J Orthop Res. 2013 Jan;31(1):91-8. doi: 10.1002/jor.22191. Epub 2012 Jul 26.


The loss of collagen organization is considered a hallmark histopathologic feature of tendinosis. At the cellular level, tenocytes have been shown to produce signal substances that were once thought to be restricted to neurons. One of the main neuropeptides implicated in tendinosis, substance P (SP), is known to influence collagen organization, particularly after injury. The aim of this study was to examine the influence of SP on collagen remodeling by primary human tendon cells cultured in vitro in three-dimensional collagen lattices. We found that SP stimulation led to an increased rate of collagen remodeling mediated via the neurokinin-1 receptor (NK-1 R), the preferred cell receptor for SP. Gene expression analysis showed that SP stimulation resulted in significant increases in MMP3, COL3A1 and ACTA2 mRNA levels in the collagen lattices. Furthermore, cyclic tensile loading of tendon cell cultures along with the administration of exogenous SP had an additive effect on MMP3 expression. Immunoblotting confirmed that SP increased MMP3 protein levels via the NK-1 R. This study indicates that SP, mediated via NK-1 R, increases collagen remodeling and leads to increased MMP3 mRNA and protein expression that is further enhanced by cyclic mechanical loading.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Achilles Tendon / cytology*
  • Achilles Tendon / physiology
  • Actins / genetics
  • Actins / metabolism
  • Biopsy
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Collagen Type III / genetics*
  • Collagen Type III / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Humans
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 3 / genetics*
  • Matrix Metalloproteinase 3 / metabolism
  • Neurotransmitter Agents / metabolism
  • Neurotransmitter Agents / pharmacology
  • Primary Cell Culture
  • Receptors, Neurokinin-1 / metabolism
  • Substance P / metabolism*
  • Substance P / pharmacology
  • Tendinopathy / drug therapy
  • Tendinopathy / genetics
  • Tendinopathy / physiopathology*
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Weight-Bearing / physiology


  • ACTA2 protein, human
  • Actins
  • COL3A1 protein, human
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Collagen Type III
  • Neurotransmitter Agents
  • Receptors, Neurokinin-1
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Substance P
  • MMP3 protein, human
  • Matrix Metalloproteinase 3
  • MMP1 protein, human
  • Matrix Metalloproteinase 1