Inhibition of apoptosis exacerbates fatigue-damage tendon injuries in an in vivo rat model

Bell, Rick; Robles-Harris, M A; Anderson, Matthew J.; Laudier, Damien M.; Schaffler, M.B.; Flatow, Evan L.; Andarawis‐Puri, Nelly

doi:10.22203/ecm.v036a04

Cited by 9 publications

(11 citation statements)

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“…Previous studies have shown that inhibition of cell apoptosis can promote tendon injury healing [48][49][50]. Indeed, the degree of cell apoptosis is closely related to the fiber structure and tissue repair.…”

Section: Discussionmentioning

confidence: 99%

Tendon stem cell-derived exosomes regulate inflammation and promote the high-quality healing of injured tendon

et al. 2020

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Background Tendon stem cells (TSCs) have been reported to hold promises for tendon repair and regeneration. However, less is known about the effects of exosomes derived from TSCs. Therefore, we aimed to clarify the healing effects of TSC-derived exosomes (TSC-Exos) on tendon injury. Methods The Achilles tendons of Sprague-Dawley male rats were used for primary culture of TSCs and tenocytes, and exosomes were isolated from TSCs. The proliferation of tenocytes induced by TSC-Exos was analyzed using an EdU assay; cell migration was measured by cell scratch and transwell assays. We used western blot to analyze the role of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. In vivo, Achilles tendon injury models were created in Sprague-Dawley rats. Rats (n = 54) were then randomly assigned to three groups: the TSC-Exos group, the GelMA group, and the control group. We used immunofluorescence to detect changes in the expression of inflammatory and apoptotic markers at 1 week after surgery. Histology and changes in expression of extracellular matrix (ECM)-related indices were assessed by hematoxylin-eosin (H&E) staining and immunohistochemistry at 2 and 8 weeks. The collagen fiber diameter of the healing tendon was analyzed at 8 weeks by transmission electron microscopy (TEM). Results TSC-Exos were taken up by tenocytes, which promoted the proliferation and migration of cells in a dose-dependent manner; this process may depend on the activation of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. At 1 week after surgery, we found that inflammation and apoptosis were significantly suppressed by TSC-Exos. At 2 and 8 weeks, tendons treated with TSC-Exos showed more continuous and regular arrangement in contrast to disorganized tendons in the GelMA and control groups, and TSC-Exos may help regulate ECM balance and inhibited scar formation. Further, at 8 weeks, the TSC-Exos group had a larger diameter of collagen compared to the control group. Conclusions Our data suggest that TSC-Exos could promote high-quality healing of injured tendon, which may be a promising therapeutic approach for tendon injury.

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Section: Discussionmentioning

confidence: 99%

Tendon stem cell-derived exosomes regulate inflammation and promote the high-quality healing of injured tendon

et al. 2020

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“…Pharmaceutical inhibition of apoptosis, using quinolyl-valyl-0-methylaspartyl-[−2, 6-difluorophenoxy]-methyl ketone (Q-VD-OPh) (SM Biochemicals LLC, Anaheim, CA), a pan-caspase inhibitor, was used to evaluate (i) whether apoptosis could be inhibited after fatigue damage and (ii) whether its inhibition could lead to production of ECM proteins that are essential for remodeling and stabilization of the micromechanical environment of the cells. 32 Retired breeder female SD rats (9-month old) received 2 or 5 days of systemic Q-VD-OPh or dimethyl sulfoxide (DMSO) carrier control injections starting immediately prior to fatigue loading. Caspase-3 staining, indicative of apoptosis, was assessed at sacrifice at 7 and 14 days post fatigue loading.…”

Section: Lessons On Remodeling Of Fatigue Injuriesmentioning

confidence: 99%

“…Systemic pan-caspase inhibition for 2 days was ineffective but inhibition for 5 days led to an increase in population of live cells. 32 Further evaluation of the 5 day group, wherein apoptosis was effectively modulated, generally showed a correlated increase in the population of cells that are producing ECM and pericellular matrix (PCM) proteins albeit in conjunction with an increase in oxidative stress markers. 32 Surprisingly, pharmaceutical inhibition of apoptosis ultimately led to exacerbation of damage of fatigue damaged tendons as indicated by further compromise in mechanical properties.…”

Section: Lessons On Remodeling Of Fatigue Injuriesmentioning

confidence: 99%

“…32 Further evaluation of the 5 day group, wherein apoptosis was effectively modulated, generally showed a correlated increase in the population of cells that are producing ECM and pericellular matrix (PCM) proteins albeit in conjunction with an increase in oxidative stress markers. 32 Surprisingly, pharmaceutical inhibition of apoptosis ultimately led to exacerbation of damage of fatigue damaged tendons as indicated by further compromise in mechanical properties. 32 While inhibition of apoptosis may still be an effective approach to promoting repair of fatigue damaged tendons, a different approach, wherein cell survival is the outcome of a modulated micro-environment of the cells, should be considered.…”

Section: Lessons On Remodeling Of Fatigue Injuriesmentioning

confidence: 99%

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Promoting effective tendon healing and remodeling

Andarawis‐Puri

Flatow

2018

Journal Orthopaedic Research

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Daily activities subject our tendons to accumulation of sub-rupture fatigue injury which can lead to tendon rupture. Consequently, tendinopathies account for over 30% of musculoskeletal consultations. We adopted a multidisciplinary approach to determine the role of the extracellular matrix (ECM) in the pathogenesis of tendinopathy and impaired healing of ruptured tendons. We have been investigating three main areas: (i) the pathogenesis of tendon degeneration; (ii) approaches to promoting remodeling of sub-rupture fatigue injuries; and the (iii) role of the ECM in promoting scarless tendon healing. In this Kappa Delta Young Investigator award paper, we describe the key discoveries made in each of our three research areas of focus. Briefly, we discovered that sub-rupture fatigue damage can accumulate from just one bout of fatigue loading. Furthermore, any attempt to repair the fatigue damage diminishes as the severity of induced damage increases. We have utilized exercise to develop animal models of exercise-led degeneration and exercise-led repair of sub-rupture fatigue damage injuries, wherein underlying mechanisms can be uncovered, thereby overcoming a major hurdle to development of therapeutics. Since damage accumulation ultimately leads to rupture that is characterized by formation of a mechanically inferior scar, we have used the MRL/MpJ mouse to evaluate the role of the systemic environment and the local tendon environment in driving regeneration to identify new therapeutic pathways to promote scarless healing. Our data suggests that the therapeutic potential of the MRL/MpJ provisional ECM should be further explored as it may harness biological and structural mechanisms to promote scarless healing. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

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“…Previous studies revealed that apoptosis plays an important role in regulating tendon regeneration during wound healing . Indeed, the extent of apoptosis positively correlates with increased fiber disorganization and diminished repair responses.…”

Section: Discussionmentioning

confidence: 99%

MFG‐E8 regulates inflammation and apoptosis in tendon healing, and promotes tendon repair: A histological and biochemical evaluation

et al. 2019

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Several studies have identified potential roles for MFG-E8 in promoting tissue repair. However, the effects of MFG-E8 on tendon repair have not yet been investigated.Therefore, we explored the role of MFG-E8 on tendon repair using a rat model of patellar tendon injury. The patellar tendons of Sprague Dawley rats (n = 24/group) received window defects and, after modeling, three groups were randomly assigned: (a) recombinant MFG-E8 (rMFG-E8) group, implantation with MFG-E8 and fibrin glue (400 ng in 10 μl); (b) fibrin group, implantation with fibrin only; and (c) control group, without any treatment. Histopathology, immunohistochemistry, and gene expression analyses were performed at 2 and 4 weeks after healing. Administration of rMFG-E8 in injury sites significantly improved tendon healing histologically at 4 weeks after injury. In addition, numbers of M1 macrophages and M1-stimulator genes, including IFNG, Il-1B, and Il-6, were reduced in the repair sites at 2 weeks by rMFG-E8 administration. In parallel, rMFG-E8 significantly increased the number of M2 macrophages and expression of anti-inflammatory IL-10 and IL-4 at 2 weeks after injury. Treatment with rMFG-E8 markedly decreased tendon cell apoptosis. Moreover, rMFG-E8 significantly enhanced the expression of genes related to tendon matrix formation at 2 weeks after injury, including Col1a1and tenascin-C. We conclude that MFG-E8 could regulate inflammatory responses and apoptotic cell accumulation in tendon repair, and promote the healing process of injured tendon tissue. Thus, exogenous application of MFG-E8 might have therapeutic potential for repair of tendon injuries. K E Y W O R D S apoptosis, healing, inflammation, MFG-E8, tendon

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Inhibition of apoptosis exacerbates fatigue-damage tendon injuries in an in vivo rat model

Cited by 9 publications

References 38 publications

Tendon stem cell-derived exosomes regulate inflammation and promote the high-quality healing of injured tendon

Tendon stem cell-derived exosomes regulate inflammation and promote the high-quality healing of injured tendon

Promoting effective tendon healing and remodeling

MFG‐E8 regulates inflammation and apoptosis in tendon healing, and promotes tendon repair: A histological and biochemical evaluation

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