Optimizing an Intermittent Stretch Paradigm Using ERK1/2 Phosphorylation Results in Increased Collagen Synthesis in Engineered Ligaments

Jennifer Z. Paxton, Paul Hagerty, Jonathan J. Andrick, Keith Baar

Research output: Contribution to journalArticlepeer-review

Abstract

Dynamic mechanical input is believed to play a critical role in the development of functional musculoskeletal tissues. To study this phenomenon, cyclic uniaxial mechanical stretch was applied to engineered ligaments using a custom-built bioreactor and the effects of different stretch frequency, amplitude, and duration were determined. Stretch acutely increased the phosphorylation of p38 (3.5 +/- 0.74-fold), S6K1 (3.9 +/- 0.19- fold), and ERK1/2 (2.45 +/- 0.32-fold). The phosphorylation of ERK1/2 was dependent on time, rather than on frequency or amplitude, within these constructs. ERK1/2 phosphorylation was similar following stretch at frequencies from 0.1 to 1Hz and amplitudes from 2.5% to 15%, whereas phosphorylation reached maximal levels at 10 min of stretch and returned toward basal within 60 min of stretch. Following a single 10-min bout of cyclic stretch, the cells remained refractory to a second stretch for up to 6 h. Using the phosphorylation of ERK1/2 as a guide, the optimum stretch paradigm was hypothesized to be 10 min of stretch at 2.5% of resting length repeated every 6 h. Consistent with this hypothesis, 7 days of stretch using this optimized intermittent stretch program increased the collagen content of the grafts more than a continuous stretch program (CTL = 3.1% +/- 0.44%; CONT=4.8% +/- 0.30%; and INT = 5.9% +/- 0.56%). These results suggest that short infrequent bouts of loading are optimal for improving engineered tendon and ligament physiology.

Original languageEnglish
Pages (from-to)277-284
Number of pages8
JournalTissue Engineering, Part A
Volume18
Issue number3-4
DOIs
Publication statusPublished - Feb 2012

Keywords

  • ANTERIOR CRUCIATE LIGAMENT
  • SIGNAL-REGULATED KINASE-1/2
  • SKELETAL-MUSCLE
  • CARDIAC FIBROBLASTS
  • MECHANICAL STRETCH
  • TENDON FIBROBLASTS
  • GENE-EXPRESSION
  • MAPK ACTIVATION
  • GROWTH-FACTORS
  • I COLLAGEN

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