In situ cell nucleus deformation in tendons under tensile load; a morphological analysis using confocal laser microscopy

Arnoczky, Steven P.; Lavagnino, Michael; Whallon, Joanne H.; Hoonjan, Amardeep

doi:10.1016/s0736-0266(01)00080-8

Cited by 136 publications

(128 citation statements)

References 47 publications

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“…9,18,21,31,32 Tensile loading of rat tail tendons has been shown to result in fluid flow, 25,26 and cellular deformations. 24 Both of these mechanisms have previously been associated with a decrease in cilia length. Fluid flow has been shown to decrease cilia lengths in renal cells 18,21,31,32 and loss of primary cilia from the endothelial surface of human umbilical cord cells.…”

Section: Discussionmentioning

confidence: 99%

“…9 While the precise mechanism(s) which trigger these changes in cilia length are unknown, it has been suggested that fluid flow and cell deformation are associated with decreases in cilia length, 9,[19][20][21] while increases in cilia length have been associated with cytoskeletal disruption. 22 Studies from our lab have shown that stress-deprivation (SD) of tendon cells has been associated with a disruption of cytoskeletal organization, 23 while tensile loading of tendons has been associated with cell deformation 24 and extracellular fluid flow. 25,26 Therefore, the purpose of the current study was to examine the effect of loading conditions on the length of primary cilia of rat tail tendon cells in situ.…”

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confidence: 99%

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Effect of in vitro stress‐deprivation and cyclic loading on the length of tendon cell cilia in situ

Gardner

Arnoczky

Lavagnino

2010

Journal Orthopaedic Research

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To determine the effect of loading conditions on the length of primary cilia in tendon cells in situ, freshly harvested rat tail tendons were stress-deprived (SD) for up to 72 h, cyclically loaded at 3% strain at 0.17 Hz for 24 h, or SD for 24 h followed by cyclic loading (CL) for 24 h. Tendon sections were stained for tubulin, and cilia measured microscopically. In fresh control tendons, cilia length ranged from 0.6 to 2.0 mm with a mean length of 1.1 mm. Following SD, cilia demonstrated an increase ( p < 0.001) in overall length at 24 h when compared to controls. Cilia length did not increase with time of SD ( p ¼ 0.329). Cilia in cyclically loaded tendons were shorter ( p < 0.001) compared to all SD time periods, but were not different from 0 time controls ( p ¼ 0.472). CL for 24 h decreased cilia length in 24 h SD tendons ( p < 0.001) to levels similar to those of fresh controls ( p ¼ 0.274). The results of this study demonstrate that SD resulted in an immediate and significant increase in the length of primary cilia of tendon cells, which can be reversed by cyclic tensile loading. This suggests that, as in other tissues, cilia length in tendon cells is affected by mechanical signaling from the extracellular matrix. Keywords: tendon cell; primary cilia; stress-deprivation; tensile loading Mechanical loading is essential for maintaining the health and homeostasis of tendons, although the fundamental mechanotransduction pathways by which cells mediate this process are unclear. 1 Primary cilia are sensory organelles for the detection and transmission of mechanical and chemical information from the extracellular environment of cells [2][3][4] and are known to function as mechanosensors in several connective tissue cell types, including tenocytes, osteocytes, and chondrocytes. [5][6][7][8][9][10][11] The expression of transmembrane extracellular matrix receptors (integrins) on the cilium strongly suggests that the cilium has the molecular machinery necessary to act as a mechanosensory linkage between the ECM and cytoplasmic organelles. 10 Bending or stretching of the cilium can tug on such integrins, thus generating a cascade of events ranging from internal calcium release 12 to the activation of genes 10 and signaling molecules. [13][14][15] However, the degree of cilia bending required to elicit a specific cellular response is unknown. 16 The primary cilium has been modeled as a cantilevered beam whose deflection, secondary to cell deformation or fluid flow, produces a mechanosensory signal to the cell. 17 As such, is it logical to assume that the longer the beam (cilium), the more sensitive it will be to smaller deflection forces and, conversely, the shorter the beam, the less sensitive it will be. 17 Indeed, previous studies have suggested that the level of mechanical stimuli experienced by a cell could lead to remodeling of its ciliary structure through changes in its length. 16 Such modifications could, theoretically, make the cilia more or less sensitive to mechanical signals transmitted by the e...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effect of in vitro stress‐deprivation and cyclic loading on the length of tendon cell cilia in situ

Gardner

Arnoczky

Lavagnino

2010

Journal Orthopaedic Research

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“…We also hypothesized this change in mechanoresponsiveness was due to an alteration in the mechanostat set point of the cells and was not a result of any substantial change in the material properties of these stress-deprived tendons. The stress-deprived in vitro system used in the current study is intended to model the destructive mechanism(s) that are thought to precede the overt pathological development of tendinopathy, namely, the catabolic response of tendon cells to the local loss of homeostatic strain as a result of isolated, microscopic collagen fiber damage [4,28]. While the concept that understimulation, rather than overstimulation, of tendon cells may be at the heart of the etiopathogenesis of tendinopathy is a new concept [5], we believe our previous investigations [3,4,33,34,36] have validated this model as a useful tool to investigate the potential role of mechanobiology in the etiopathogenesis of tendinopathy.…”

Section: Discussionmentioning

confidence: 99%

“…The stress-deprived in vitro system used in the current study is intended to model the destructive mechanism(s) that are thought to precede the overt pathological development of tendinopathy, namely, the catabolic response of tendon cells to the local loss of homeostatic strain as a result of isolated, microscopic collagen fiber damage [4,28]. While the concept that understimulation, rather than overstimulation, of tendon cells may be at the heart of the etiopathogenesis of tendinopathy is a new concept [5], we believe our previous investigations [3,4,33,34,36] have validated this model as a useful tool to investigate the potential role of mechanobiology in the etiopathogenesis of tendinopathy. The increase in MMP-13 mRNA expression and protein synthesis seen in this model [2,5,[33][34][35][36], as well as the histological features of cell shape change [21] and apoptosis [2,12], which accompany loss of homeostatic strain, are very similar to those changes reported in clinical cases of tendinopathy [1, 2, 5, 19, 24, 26, 28, 30, 31, 38-40, 45, 50, 54, 60, 61].…”

Section: Discussionmentioning

confidence: 99%

Loss of Homeostatic Strain Alters Mechanostat “Set Point” of Tendon Cells In Vitro

Arnoczky

Lavagnino

Egerbacher

et al. 2008

Clinical Orthopaedics &Amp; Related Research

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Tendon cells respond to mechanical loads. The character (anabolic or catabolic) and sensitivity of this response is determined by the mechanostat set point of the cell, which is governed by the cytoskeleton and its interaction with the extracellular matrix. To determine if loss of cytoskeletal tension following stress deprivation decreases the mechanoresponsiveness of tendon cells, we cultured rat tail tendons under stress-deprived conditions for 48 hours and then cyclically loaded them for 24 hours at 1%, 3%, or 6% strain at 0.17 Hz. Stress deprivation upregulated MMP-13 mRNA expression and caused progressive loss of cellmatrix contact compared to fresh controls. The application of 1% strain to fresh tendons for 24 hours inhibited MMP-13 mRNA expression compared to stress-deprived tendons over the same period. However, when tendons were stressdeprived for 48 hours and then subjected to the same loading regime, the inhibition of MMP-13 mRNA expression was decreased. In stress-deprived tendons, it was necessary to increase the strain magnitude to 3% to achieve the same level of MMP-13 mRNA inhibition seen in fresh tendons exercised at 1% strain. The data suggest loss of cytoskeletal tension alters the mechanostat set point and decreases the mechanoresponsiveness of tendon cells.

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“…The responsiveness of connective tissue cells such as osteoblasts, chondrocytes and fibroblasts to mechanical strain has been confirmed by several in vitro investigations and the effect of cyclic strain on tendon cells has been associated with a diverse array of biological responses [ 1- 3,6,5,12,19,24,30,38,46,47,49,53,54]. These cellular features are necessary to restore the normal mechanical properties of the tissue after injury or during a remodeling process (e.g.…”

Section: Discussionmentioning

confidence: 99%

Cyclic strain influences the expression of the vascular endothelial growth factor (VEGF) and the hypoxia inducible factor 1 alpha (HIF‐1α) in tendon fibroblasts

Petersen

Varoga

Zantop

et al. 2004

Journal Orthopaedic Research

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Neovascularization is involved in beneficial and detrimental processes of tendon pathology. We investigated the influence of repetitive motion on the expression of the most important angiogenic factor, the vascular endothelial growth factor (VEGF) in the 3T3 NIH fibroblast cell line and in cultures of rat Achilles tendon fibroblasts. Monolayers of subconfluently grown cells were stretched in rectangular silicone dishes with cyclic uniaxial movement. Strain was applied over 24 h varying the frequency (0.5–1 Hz). Fibroblasts (3T3 fibroblasts and rat Achilles tendon cultures) cultivated without the application of cyclic strain released measurable VEGF amounts into their culture supernatants. Cyclic stretching of the cells with a frequency of 1 Hz resulted in an increased expression of VEGF. A low frequency (0.5 Hz) reduced VEGF expression to control levels. RT PCR revealed VEGF 121 and VEGF 165 as the only splice forms that were induced by cyclic stretching. Western blot experiments could further show that cyclic stretching induced activation of the transcription factor HIF‐1α. These results demonstrate that mechanical factors are involved in the regulation of VEGF expression in tendon tissue. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

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In situ cell nucleus deformation in tendons under tensile load; a morphological analysis using confocal laser microscopy

Cited by 136 publications

References 47 publications

Effect of in vitro stress‐deprivation and cyclic loading on the length of tendon cell cilia in situ

Effect of in vitro stress‐deprivation and cyclic loading on the length of tendon cell cilia in situ

Loss of Homeostatic Strain Alters Mechanostat “Set Point” of Tendon Cells In Vitro

Cyclic strain influences the expression of the vascular endothelial growth factor (VEGF) and the hypoxia inducible factor 1 alpha (HIF‐1α) in tendon fibroblasts

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