Ex vivo static tensile loading inhibits MMP‐1 expression in rat tail tendon cells through a cytoskeletally based mechanotransduction mechanism

Arnoczky, Steven P.; Tian, Tian; Lavagnino, Michael; Gardner, Keri

doi:10.1016/s0736-0266(03)00185-2

Cited by 154 publications

(192 citation statements)

References 32 publications

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“…Since metalloproteinase expression in tendon cells is known to be modulated by mechanical loading (31)(32)(33)(34), it is possible, given the absence of inflammation in most specimens, that at least some of the changes in gene expression described herein are induced by an altered mechanical environment. Remodeling of the tendon matrix may be induced by increased levels of strain and shear or compressive forces acting on the tissue.…”

Section: Discussionmentioning

confidence: 96%

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Jones¹,

Corps²,

Pennington³

et al. 2006

Arthritis & Rheumatism

256

283

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Objective. To profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons.Methods. Tendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real-time reverse transcription-polymerase chain reaction, normalized to 18S ribosomal RNA.Results. In comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P < 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP-3 and higher levels of ADAM-12 and MMP-23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP-1 in ruptured compared with normal tendons.Conclusion. The distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon.

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Section: Discussionmentioning

confidence: 96%

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Jones¹,

Corps²,

Pennington³

et al. 2006

Arthritis & Rheumatism

256

283

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“…22 Previous studies from our lab have shown that fluid flow in tendons occurs in response to tensile loading 25,27 and SD of tendon cells results in an immediate disruption of the actin cytoskeleton in these cells. 23 While the presence or absence of physical signals appears to be related to changes in cilia length, the precise mechanism(s) and pathways involved in mediating these changes are unknown. In addition to changes in cilia length, alterations in ciliary membrane structure in response to mechanical or chemical signals may also occur.…”

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%

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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“…MMPs are also implicated in the remodelling of tendon that follows immobilisation (Refs 126,127,128,129). MMP-1 is thought to be one of the key mediators of tendon fibrillar collagen degradation, at least in explant culture, and this activity can be inhibited by the application of cyclical strain, an effect though to be mediated via the tenocyte cytoskeleton ( Refs 130,131,132,133,134). Isolated tenocytes respond to strain and shear forces by Several MMPs have been identified in acute tendon injuries, with differences in the timing and location of expression that suggest different roles in the healing process.…”

Section: Mmps In Tendonmentioning

confidence: 99%

Chronic tendon pathology: molecular basis and therapeutic implications

Riley

2005

Expert Rev. Mol. Med.

103

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Tendons are frequently affected by chronic pain or rupture. Many causative factors have been implicated in the pathology, which until relatively recently was under-researched and poorly understood. There is now a greater knowledge of the molecular basis of tendon disease. Most tendon pathology (tendinopathy) is associated with degeneration, which is thought to be an active, cell-mediated process involving increased turnover and remodelling of the tendon extracellular matrix. Degradation of the tendon matrix is mediated by a variety of metalloproteinase enzymes, including matrix metalloproteinases and 'aggrecanases'. Neuropeptides and other factors released by stimulated cells or nerve endings in or around the tendon might influence matrix turnover, and could provide novel targets for therapeutic intervention.Tendons are dense, fibrous connective tissues that connect muscle to bone and are essential for the transmission of force and the generation of movement at a joint. They are highly ordered composite materials consisting of collagens, proteoglycans and various glycoproteins, many of which have been poorly characterised. Tendon problems such as tendon rupture and chronic tendon pain are common, although the underlying pathology is not well understood and the conditions are often difficult to treat (Ref.

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Ex vivo static tensile loading inhibits MMP‐1 expression in rat tail tendon cells through a cytoskeletally based mechanotransduction mechanism

Cited by 154 publications

References 32 publications

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

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

Chronic tendon pathology: molecular basis and therapeutic implications

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