Year-end Sale % OFF 
Abstract
Rotator cuff tears represent a large burden of muscle-tendon injuries in our aging population. While small tears can be repaired surgically with good outcomes, critical size tears are marked by muscle atrophy, fibrosis, and fatty infiltration, which can lead to failed repair, frequent re-injury, and chronic disability. Previous animal studies have indicated that Transforming Growth Factor-β (TGF-β) signaling may play an important role in the development of these muscle pathologies after injury. Here, we demonstrated that inhibition of TGF-β1 signaling with the small molecule inhibitor SB431542 in a mouse model of massive rotator cuff tear results in decreased fibrosis, fatty infiltration, and muscle weight loss. These observed phenotypic changes were accompanied by decreased fibrotic, adipogenic, and atrophy-related gene expression in the injured muscle of mice treated with SB431542. We further demonstrated that treatment with SB431542 reduces the number of fibro/adipogenic progenitor (FAP) cells—an important cellular origin of rotator cuff muscle fibrosis and fatty infiltration, in injured muscle by promoting apoptosis of FAPs. Together, these data indicate that the TGF-β pathway is a critical regulator of the degenerative muscle changes seen after massive rotator cuff tears. TGF-β promotes rotator cuff muscle fibrosis and fatty infiltration by preventing FAP apoptosis. TGF-β regulated FAP apoptosis may serve as an important target pathway in the future development of novel therapeutics to improve muscle outcomes following rotator cuff tear.
Highlights
Rotator cuff (RC) tears are among the most common muscle-tendon injuries in our aging population, with an asymptomatic tear prevalence of 20% in patients aged 60–70 and a prevalencePLOS ONE | DOI:10.1371/journal.pone.0155486 May 17, 2016Inhibition of Transforming Growth Factor-β (TGF-β) Signaling in a Mouse Model of Rotator Cuff Tear
Our previous work demonstrated significant up-regulation of TGF-β1 signaling in rotator cuff muscle after massive tendon tears, suggesting this pathway may play a critical role in rotator cuff muscle pathology [16]
We tested the feasibility of a small molecule TGF-β1 inhibitor, SB431542, in preventing rotator cuff atrophy, fibrosis and fatty infiltration in a preclinical mouse model of RC tear
Summary
Rotator cuff (RC) tears are among the most common muscle-tendon injuries in our aging population, with an asymptomatic tear prevalence of 20% in patients aged 60–70 and a prevalence. It has been shown to be active in the setting of a combined tendon-nerve injury in rats, and to correlate with increased fibrosis and fatty infiltration of injured muscle [16]. Prior studies have likewise shown a correlation between p-SMAD2 activation and muscle fibrosis [13,15] For these reasons, the canonical TGF-β pathway has been proposed as a master regulator of the fibrotic changes seen in muscle in chronic injury states. We sought to test the feasibility of preventing rotator cuff muscle fatty infiltration and fibrosis using a small molecule TGF-β inhibitor SB431542 in a mouse model of RC tears. We hypothesized that inhibition of TGF-β signaling with SB431542 would result in prevention of fibrosis and fatty infiltration after a massive RC tear, and that this process may be mediated by the impact of TGF-β signaling on FAP cell number
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
