Upregulation of transforming growth factor-β signaling in a rat model of rotator cuff tears

Liu, Xuhui; Joshi, Sunil; Ravishankar, Bharat; Laron, Dominique; Kim, Hubert T.; Feeley, Brian T.

doi:10.1016/j.jse.2014.02.029

Cited by 42 publications

(47 citation statements)

References 34 publications

(54 reference statements)

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“…The near‐significant increase in TGF‐β1 expression seen with LPA treatment may be related to the increase in monocyte‐derived inflammatory cells present in injured muscle. Macrophages are thought to be a key source of TGF‐β1 in chronically injured muscle, and TGF‐β1 signaling has been linked to increased fibrosis within the RC of rats and increased fibrofatty infiltration in mice . Inhibition of TGF‐β1 signaling in mice has likewise shown a reduction in RC muscle atrophy and fibrofatty infiltration by decreasing the number of fibro/adipogenic progenitor cells present in injured muscle .…”

Section: Discussionmentioning

confidence: 99%

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Lysophosphatidic acid-induced RhoA signaling and prolonged macrophage infiltration worsens fibrosis and fatty infiltration following rotator cuff tears

et al. 2016

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Previous studies have suggested that macrophage-mediated chronic inflammation is involved in the development of rotator cuff muscle atrophy and degeneration following massive tendon tears. Increased RhoA signaling has been reported in chronic muscle degeneration, such as muscular dystrophy. However, the role of RhoA signaling in macrophage infiltration and rotator muscle degeneration remains unknown. Using a previously established rat model of massive rotator cuff tears, we found RhoA signaling is upregulated in rotator cuff muscle following a massive tendon-nerve injury. This increase in RhoA expression is greatly potentiated by the administration of a potent RhoA activator, lysophosphatidic acid (LPA), and is accompanied by increased TNFα and TGF-β1 expression in rotator cuff muscle. Boosting RhoA signaling with LPA significantly worsened rotator cuff muscle atrophy, fibrosis, and fatty infiltration, accompanied with massive monocytic infiltration of rotator cuff muscles. Co-staining of RhoA and the tissue macrophage marker CD68 showed that CD68+ tissue macrophages are the dominant cell source of increased RhoA signaling in rotator cuff muscles after tendon tears. Taken together, our findings suggest that LPA-mediated RhoA signaling in injured muscle worsens the outcomes of atrophy, fibrosis, and fatty infiltration by increasing macrophage infiltraion in rotator cuff muscle. Clinically, inhibiting RhoA signaling may represent a future direction for developing new treatments to improve muscle quality following massive rotator cuff tears.

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Section: Discussionmentioning

confidence: 99%

“…Sixteen adult female Sprague–Dawley rats underwent complete supraspinatus and infraspinatus tendon transection (TT) with a 5 mm ipsilateral suprascapular nerve resection (DN), as previously described . Sham surgery was performed on the contralateral side of each animal.…”

Section: Methodsmentioning

confidence: 99%

Lysophosphatidic acid-induced RhoA signaling and prolonged macrophage infiltration worsens fibrosis and fatty infiltration following rotator cuff tears

et al. 2016

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“…A recent study showed that BMP-14 inhibits MMP-13 expression in chondrocytes 21 . In our previous work, we have shown significantly increased TGFβ 22 and BMP 23 signaling in rotator cuff muscles after massive tendon tears, suggesting TGFβ/BMP signaling may be involved in rotator cuff muscle fatty degeneration through regulating MMP-13 expression. Future works are needed to define the role of TGFβ/BMP signaling in regulating MMP-13 in RC muscles.…”

Section: Discussionmentioning

confidence: 89%

Knocking-out matrix metalloproteinase-13 exacerbates rotator cuff muscle fatty infiltration

Liu

Ravishankar

Ning

et al. 2017

MLTJ

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SummaryIntroduction: Rotator cuff (RC) tears are common tendon injuries. Clinically, both muscle atrophy and fatty infiltration have generally been attributed to poor functional outcomes. Matrix metalloproteinase-13 plays a crucial role in extracellular matrix remodeling in many physiological and pathological processes. Nevertheless, its role in rotator cuff muscle atrophy and fatty infiltration remains unknown. The purpose of this study is to define the functional role of MMP-13 in rotator cuff muscle atrophy and fatty infiltration using a mouse RC tears model. Materials and methods: Unilateral complete supraspinatus and infraspinatus tendon transection and suprascapular nerve transection was performed on nine of MMP-13 (-/-) knockout and nine of MMP-13 (+/+) wildtype mice at 3 months old. Mice were sacrificed 6 weeks after surgery. Supraspinatus (SS) and infraspinatus (IS) muscles were harvested for histology and gene expression analysis with RT-PCR. Results: Six weeks after RC surgery, no significant difference in muscle atrophy and fibrosis between MMP-13 knockout and wild type mice was observed. However, there was a significant increase in the amount of fatty infiltration in MMP-13 knockout mice compared to the wild types. Muscles from MMP-13 knockout mice have significantly higher expression of fatty infiltration related genes.

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“…qRT-PCR was performed to quantify the expression of aSMA 25,26 , Col-1 26 , Col-3 26 , MuRF-1 11,27 , MAFbx 11, 27 , MMP-13 28,29 , PPARg, and SREBP-1 using a Light Cycler 480 SYBR Green I Master kit (Roche Applied Bioscience Inc.). Primer sequences are listed in Table 1.…”

Section: Quantitative Reverse Transcription Polymerase Chain Reactionmentioning

confidence: 99%

Muscle atrophy and fatty infiltration after an acute rotator cuff repair in a sheep model

Liu

Easley

Ravishankar

et al. 2015

MLTJ

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Muscle atrophy and fatty infiltration after an acute rotator cuff repair in a sheep model tration, and fibrosis related genes. Significantly increased adipocytes, muscle fatty infiltration, and collagen deposition was observed in rotator cuff muscles in the tendon repair group compared to the control group. Conclusions: rotator cuff muscle undergoes degradation changes including fatty infiltration and fibrosis even after the tendons are repair immediately after rupture. Level of Evidence: Basic Science Study. IntroductionRotator cuff tears (RCTs) are the most common shoulder injury seen by orthopedic surgeons and are especially frequent among the aging patient population. The prevalence of full thickness RCTs is estimated between 15 and 51%, with higher rates in the elderly population 1 . Although repair of small tears is successful in alleviating pain and improving shoulder biomechanics, successful repair of larger RCTs still remains a challenge 2,3 . As the incidence of rotator cuff injuries continues to rise with an aging patient population, management and knowledge of the etiopathogenesis of RCTs 4 is a topic of concern. Several muscle-based factors have been identified to affect the outcome of rotator cuff repairs. It has been demonstrated that the degree of atrophy correlates with the size of the tear and, more importantly, with clinical outcomes 5,6 . Similarly, fatty infiltration has been shown to also correlate with poor outcomes following rotator cuff repair 6,7 . Although the clinical effects of muscle fibrosis on rotator cuff injuries are not well quantified, muscle fibrosis is an important contributor to muscle stiffness and is seen in many other muscle injury models 8 . Thus, these three physiological traits, muscle atrophy, fatty infiltration, and muscle fibrosis, are likely key factors governing outcome after rotator cuff injury and repair. Animal models are useful tools to study the molecular mechanisms of muscle atrophy, fatty infiltration, and fibrosis that are observed in the setting of rotator cuff tears in patients. While there are multiple RCTs studies conducted in rat or mouse models 9-12 , the sheep model, as a larger animal model, may more closely mirror the pathophysiologic changes observed in human RCTs 13 since the infraspinatus tendons of sheep SummaryIntroduction: rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Muscle atrophy and fatty infiltration of the muscle are crucial factors that dictate the outcome following rotator cuff surgery. Though less studied in humans, rotator cuff muscle fibrosis has been seen in animal models as well and may influence outcomes as well. The purpose of this study was to determine if the rotator cuff would develop muscle changes even in the setting of an acute repair in a sheep model. We hypothesized that fatty infiltration and fibrosis would be present even after an acute repair six months after initial surgery. Methods: twelve female adult sheep underwent an acute rotator cuff tear and immediate repair on ...

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Upregulation of transforming growth factor-β signaling in a rat model of rotator cuff tears

Cited by 42 publications

References 34 publications

Lysophosphatidic acid-induced RhoA signaling and prolonged macrophage infiltration worsens fibrosis and fatty infiltration following rotator cuff tears

Lysophosphatidic acid-induced RhoA signaling and prolonged macrophage infiltration worsens fibrosis and fatty infiltration following rotator cuff tears

Knocking-out matrix metalloproteinase-13 exacerbates rotator cuff muscle fatty infiltration

Muscle atrophy and fatty infiltration after an acute rotator cuff repair in a sheep model

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