title: Protease-activated receptors in the Achilles tendon-a potential explanation for the excessive pain signalling in tendinopathy.
abstract: OBJECTIVE
  Tendinopathies are pathological conditions of tissue remodelling occurring in the major tendons of the body, accompanied by excessive nociceptive signalling. Tendinopathies have been shown to exhibit an increase in the number of mast cells, which are capable of releasing histamine, tryptase and other substances upon activation, which may play a role in the development of tendinopathies. This study set out to describe the distribution patterns of a family of receptors called protease-activated receptors (PARs) within the Achilles tendon. These four receptors (PAR1, PAR2, PAR3, PAR4) are activated by proteases, including tryptase released from mast cells, and are involved in fibrosis, hyperalgesia and neovascularisation, which are changes seen in tendinopathies.
  
  
  METHODS
  In order to study which structures involved in tendinopathy that these proteases can affect, biopsies from patients suffering of mid-portion Achilles tendinosis and healthy controls were collected and examined using immunohistochemistry. Tendon cells were cultured to study in vitro expression patterns.
  
  
  RESULTS
  The findings showed a distribution of PARs inside the tendon tissue proper, and in the paratendinous tissue, with all four being expressed on nerves and vascular structures. Double staining showed co-localisation of PARs with nociceptive fibres expressing substance P. Concerning tenocytes, PAR2, PAR3, and PAR4, were found in both biopsies of tendon tissue and cultured tendon cells.
  
  
  CONCLUSIONS
  This study describes the expression patterns of PARs in the mid-portion of the Achilles tendon, which can help explain the tissue changes and increased pain signalling seen in tendinopathies. These findings also show that in-vitro studies of the effects of these receptors are plausible and that PARs are a possible therapeutic target in the future treatment strategies of tendinopathy.
authors.affiliation: Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, SE-90187, Sweden. jech0003@gmail.com.
authors.forename: Jens
authors.initials: J
authors.lastname: Christensen
authors.affiliation: Department of Community Medicine and Rehabilitation, Sports Medicine, Umeå University, Umeå, SE-90187, Sweden. hakan.alfredson@idrott.umu.se.|ISEH, UCLH, London, UK. hakan.alfredson@idrott.umu.se.|Pure Sports Clinic, London, UK. hakan.alfredson@idrott.umu.se.
authors.forename: Håkan
authors.initials: H
authors.lastname: Alfredson
authors.affiliation: Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, SE-90187, Sweden. gustav.andersson@umu.se.|Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Umeå University, Umeå, SE-90187, Sweden. gustav.andersson@umu.se.
authors.forename: Gustav
authors.initials: G
authors.lastname: Andersson
mesh_terms: D000125:Achilles Tendon / Q000378:metabolism*; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000378:metabolism*; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D052256:Tendinopathy / Q000378:metabolism*
chemical_list: D044462:Receptors, Proteinase-Activated; D013373:Substance P