title: Tenocyte responses to mechanical loading in vivo: a role for local insulin-like growth factor 1 signaling in early tendinosis in rats.
abstract: OBJECTIVE
  To investigate tenocyte regulatory events during the development of overuse supraspinatus tendinosis in rats.
  
  
  METHODS
  Supraspinatus tendinosis was induced by running rats downhill at 1 km/hour for 1 hour a day. Tendons were harvested at 4, 8, 12, and 16 weeks and processed for brightfield, polarized light, or transmission electron microscopy. The development of tendinosis was assessed semiquantitatively using a modified Bonar histopathologic scale. Apoptosis and proliferation were examined using antibodies against fragmented DNA or proliferating cell nuclear antigen, respectively. Insulin-like growth factor 1 (IGF-1) expression was determined by computer-assisted quantification of immunohistochemical reaction. Local IGF-1 signaling was probed using antibodies to phosphorylated insulin receptor substrate 1 (IRS-1) and ERK-1/2.
  
  
  RESULTS
  Tendinosis was present after 12 weeks of downhill running and was characterized by tenocyte rounding and proliferation as well as by glycosaminoglycan accumulation and collagen fragmentation. The proliferation index was elevated in CD90+ tenocytes in association with tendinosis and correlated with increased local IGF-1 expression by tenocytes and phosphorylation of IRS-1 and ERK-1/2. Both apoptosis and cellular inflammation were absent at all time points.
  
  
  CONCLUSIONS
  In this animal model, early tendinosis was associated with local stimulation of tenocytes rather than with extrinsic inflammation or apoptosis. Our data suggest a role for IGF-1 in the load-induced tenocyte responses during the pathogenesis of overuse tendon disorders.
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scott
authors.forename: Jill L
authors.initials: JL
authors.lastname: Cook
authors.forename: David A
authors.initials: DA
authors.lastname: Hart
authors.forename: David C
authors.initials: DC
authors.lastname: Walker
authors.forename: Vincent
authors.initials: V
authors.lastname: Duronio
authors.forename: Karim M
authors.initials: KM
authors.lastname: Khan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001696:Biomechanical Phenomena; D049109:Cell Proliferation; D012090:Cumulative Trauma Disorders / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D052256:Tendinopathy / Q000209:etiology / Q000503:physiopathology*; D013710:Tendons / Q000166:cytology / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D048052:Mitogen-Activated Protein Kinase 3