PMID- 26549105 OWN - NLM STAT- MEDLINE DCOM- 20161024 LR - 20190111 IS - 1528-8951 (Electronic) IS - 0148-0731 (Print) IS - 0148-0731 (Linking) VI - 138 IP - 2 DP - 2016 Feb TI - Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction. PG - 021013 LID - 10.1115/1.4031975 [doi] AB - Excessive loading of ligaments can activate the neural afferents that innervate the collagenous tissue, leading to a host of pathologies including pain. An integrated experimental and modeling approach was used to define the responses of neurons and the surrounding collagen fibers to the ligamentous matrix loading and to begin to understand how macroscopic deformation is translated to neuronal loading and signaling. A neuron-collagen construct (NCC) developed to mimic innervation of collagenous tissue underwent tension to strains simulating nonpainful (8%) or painful ligament loading (16%). Both neuronal phosphorylation of extracellular signal-regulated kinase (ERK), which is related to neuroplasticity (R2 >/= 0.041; p /= 0.250; p < 0.0001), were significantly correlated with tissue-level strains. As NCC strains increased during a slowly applied loading (1%/s), a "switchlike" fiber realignment response was detected with collagen reorganization occurring only above a transition point of 11.3% strain. A finite-element based discrete fiber network (DFN) model predicted that at bulk strains above the transition point, heterogeneous fiber strains were both tensile and compressive and increased, with strains in some fibers along the loading direction exceeding the applied bulk strain. The transition point identified for changes in collagen fiber realignment was consistent with the measured strain threshold (11.7% with a 95% confidence interval of 10.2-13.4%) for elevating ERK phosphorylation after loading. As with collagen fiber realignment, the greatest degree of neuronal reorientation toward the loading direction was observed at the NCC distraction corresponding to painful loading. Because activation of neuronal ERK occurred only at strains that produced evident collagen fiber realignment, findings suggest that tissue strain-induced changes in the micromechanical environment, especially altered local collagen fiber kinematics, may be associated with mechanotransduction signaling in neurons. FAU - Zhang, Sijia AU - Zhang S FAU - Cao, Xuan AU - Cao X FAU - Stablow, Alec M AU - Stablow AM FAU - Shenoy, Vivek B AU - Shenoy VB FAU - Winkelstein, Beth A AU - Winkelstein BA LA - eng GR - R01 EB017753/EB/NIBIB NIH HHS/United States GR - U01 EB016638/EB/NIBIB NIH HHS/United States GR - R01EB017753/EB/NIBIB NIH HHS/United States GR - U01EB016638/EB/NIBIB NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - J Biomech Eng JT - Journal of biomechanical engineering JID - 7909584 RN - 9007-34-5 (Collagen) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Biomechanical Phenomena MH - Collagen/*metabolism MH - Extracellular Signal-Regulated MAP Kinases/*metabolism MH - Ligaments/*injuries/physiology MH - *Mechanotransduction, Cellular MH - Neurons/*cytology/*metabolism MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - *Stress, Mechanical MH - Weight-Bearing PMC - PMC4844078 EDAT- 2015/11/10 06:00 MHDA- 2016/10/25 06:00 PMCR- 2017/02/01 CRDT- 2015/11/10 06:00 PHST- 2015/08/05 00:00 [received] PHST- 2015/11/10 06:00 [entrez] PHST- 2015/11/10 06:00 [pubmed] PHST- 2016/10/25 06:00 [medline] PHST- 2017/02/01 00:00 [pmc-release] AID - 2469752 [pii] AID - BIO-15-1392 [pii] AID - 10.1115/1.4031975 [doi] PST - ppublish SO - J Biomech Eng. 2016 Feb;138(2):021013. doi: 10.1115/1.4031975.