Bone morphogenetic protein signaling in rotator cuff muscle atrophy and fatty infiltration

Liu, X.; Joshi, S.K.; Ravishankar, Bharat; Laron, Dominique; Kim, H.T.

doi:10.32098/mltj.02.2015.10

Cited by 12 publications

(9 citation statements)

References 19 publications

(21 reference statements)

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“…In humans, it is theorized that injury to the rotator cuff creates increased tension on the suprascapular nerve, which places the nerve at risk for injury 28 . This is a different mechanism of injury to the nerve than is seen clinically in rotator cuff tears; however, this mouse model has been shown to mimic pathophysiologic changes seen after a rotator cuff injury in previous studies 18,29 . In summary, results from this study suggest that Tie2 + progenitor cells are the major source of fibroblasts and FAPs are the major cellular source of adipocytes in RC muscle following tendon tears.…”

Section: Discussionmentioning

confidence: 97%

Investigating the cellular origin of rotator cuff muscle fatty infiltration and fibrosis after injury

Liu

Ning

Chang

et al. 2019

Muscle Ligaments and Tendons J

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Background: rotator cuff muscle atrophy, fibrosis and fatty infiltration are common complications after large and massive rotator cuff tears. Currently, there are no effective treatments for these muscle pathologies after injury. Furthermore, the cellular source for fibrotic and adipose tissues in rotator cuff muscle after injury remains unknown. In this study, we proposed that two groups of muscle resident progenitors, Tie2+ muscle mesenchymal progenitors and PDGFRα + fibro/adipogenic progenitor cells (FAPs), contribute significantly to rotator cuff muscle fibrosis and fatty infiltration. Methods: we tested our hypothesis using reporter mice. Rotator cuff muscles from Tie2-GFP and PDGFRα-GFP reporter mice were harvested at 2 and 6 weeks after unilateral massive rotator cuff tear surgeries. Immunofluorescent staining for fibroblast and adipocyte markers was conducted. Results: our results showed significant co-localization of Tie2+ cells with fibrotic markers vimentin and αSMA. In the PDGFRα-GFP reporter mice, GFP signal was seen in only a small fraction of cells staining positive for vimentin and αSMA. However, PDGFRα showed significant co-localization with adipocyte markers, including PPAR-γ, adiponectin, and perilipin A. Oil red O staining confirmed that the mature adipocytes appearing in rotator cuff muscles after injury are also PDGFRα +. Conclusion: these data demonstrated that the Tie2 + muscle mesenchymal progenitors are the major source of fibroblasts while PDGFRα + FAPs are the major source of adipocytes in rotator cuff muscle fatty infiltration. Basic Science Study.

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Section: Discussionmentioning

confidence: 97%

Investigating the cellular origin of rotator cuff muscle fatty infiltration and fibrosis after injury

Liu

Ning

Chang

et al. 2019

Muscle Ligaments and Tendons J

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“…Five fields of view were analysed per sample to determine the percentage of muscle fibre coverage, as determined by the percentage of pink staining fibres in the field of view. This was performed using the Image J software; images were first converted to 8 bit, followed by thresholding and manual image adjustment to accurately measure muscle coverage area [35].…”

Section: Histological Evaluationmentioning

confidence: 99%

Modelling gluteus medius tendon degeneration and repair in a large animal model

Zhu

Musson

Oliver

et al. 2020

Arch Orthop Trauma Surg

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Introduction Gluteus medius tendon tears often occur in the context of chronic tendinopathy and remain a difficult clinical problem. Surgical repair is challenging as it is often delayed and performed in degenerative tendons. No animal model currently exists to mimic the delayed repair of tendinopathic gluteus medius tears. The aims of this study were to develop a chronic model of gluteus medius tendinopathy and tear and then compare this model to an acute gluteus medius tear and repair. Materials and methods Six gluteus medius muscles were dissected and examined in mature sheep to confirm anatomical similarity to the human counterpart. Ten separate adult sheep underwent tendon detachment, followed by relook and histological sampling at 6 and 16 weeks to assess the extent of tendon degeneration. Six adult sheep underwent tendon repair at 6 weeks and were later assessed for healing of the tendon and compared to a further four adult sheep who underwent an acute tendon detachment and repair procedure. Results The sheep gluteus medius muscle consisted of three compartments, the anterior, middle and posterior. All compartments inserted via the common tendon on the superolateral aspect of the greater trochanter. At both 6 and 16 weeks, there was significant tendinopathic changes on histology compared to controls as assessed by modified Movin's score (p = 0.018, p = 0.047) but no difference between the 6-and 16-week groups (p = 0.25). There were significant differences between delayed and acute repair in both histological appearance (p = 0.025) and biomechanical properties (p = 0.019), with acute repair superior in both. Conclusions Tendon detachment for 6 weeks is sufficient to produce histological changes similar to chronic tendinopathy and repair of this degenerative tendon results in significantly poorer healing when compared to an acute repair model. Animal models for gluteus medius tears should use a delayed repair model to improve clinical validity.

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“…Canonical TGFβ and BMP pathway share the common downstream Smads factors, although TGFβ prefers Smad2/3 and BMP prefers Samd1/5/8 43 . Our previous studies have shown two important TGFβ and BMP family members—TGFβ‐1 9 and BMP‐7 10 are overexpressed in muscle after RC injury. In this study, we showed that TGFβ‐1 suppresses FAP adipogenesis while BMP‐7 promotes FAP adipogenesis.…”

Section: Discussionmentioning

confidence: 98%

“…Transforming growth factor beta (TGFβ) and bone morphogenetic protein‐7 (BMP‐7) have been found to play important roles in stem cell adipogenesis 8 . In our previous studies, we observed significantly increased TGFβ and BMP‐7 during the development of muscle fatty infiltrated after RC tears 9,10 . Inhibition TGFβ and BMP pathways decrease RC muscle FI after massive tendon tears 11 .…”

Section: Introductionmentioning

confidence: 94%

Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

Liu

Lee

et al. 2020

Journal Orthopaedic Research

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Rotator cuff (RC) muscle fatty infiltration (FI) is an important factor that determines the clinical outcome of patients with RC repair. There is no effective treatment for RC muscle FI at this time. The goal of this study is to define the role Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor in regulating muscle fibro/adipogenic progenitors (FAPs) adipogenesis and treating muscle fatty degeneration after massive RC tears in a mouse model. We hypothesize that TSA reduces muscle FI after massive RC tears. HDAC activity was measured in FAPs in RC muscle after tendon/nerve transection or sham surgery. FAPs were treated with TSA for 2 weeks and FAP adipogenesis was evaluated with perilipin and Oil Red O staining, as well as reverse transcript‐polymerase chain reaction for adipogenesis‐related genes. About 0.5 mg/kg TSA or dimethyl sulfoxide was administered to C57B/L6 mice with massive rotator cuff tears through daily intraperitoneal injection for 6 weeks. Supraspinatus muscles were harvested for biochemical and histology analysis. We found that FAPs showed significantly higher HDAC activity after RC tendon/nerve transection. TSA treatment significantly reduced HDAC activity and inhibited adipogenesis of FAPs. TSA also abolished the role of bone morphogenetic protein‐7 in inducing FAP adipogenesis and promoted FAP brown/beige adipose tissue (BAT) differentiation. TSA injection significantly increased histone H3 acetylation and reduced FI of rotator cuff muscles after massive tendon tears. Results from this study showed that TSA can regulate FAP adipogenesis and promote FAP BAT differentiation epigenetically. HDAC inhibition may be a new treatment strategy to reduce muscle FI after RC tears and repair.

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Bone morphogenetic protein signaling in rotator cuff muscle atrophy and fatty infiltration

Abstract: Conclusion: this result suggests that BMP signaling inhibits RC muscle atrophy but promotes fatty infiltration.

Cited by 12 publications

References 19 publications

Investigating the cellular origin of rotator cuff muscle fatty infiltration and fibrosis after injury

Investigating the cellular origin of rotator cuff muscle fatty infiltration and fibrosis after injury

Modelling gluteus medius tendon degeneration and repair in a large animal model

Trichostatin A regulates fibro/adipogenic progenitor adipogenesis epigenetically and reduces rotator cuff muscle fatty infiltration

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