Inhibition of p38 mitogen-activated protein kinase signaling reduces fibrosis and lipid accumulation after rotator cuff repair

Abstract

Background The repair of rotator cuff tears is often complicated by fatty degeneration, which is the combination of lipid accumulation, fibrosis, inflammation and muscle weakness. p38 MAPK is a signaling molecule that plays a central role in these processes. The purpose of this study was to evaluate a small molecule inhibitor of p38 MAPK, SB203580, in reducing fatty degeneration in a preclinical model of rotator cuff injury and repair. Methods Adult rats underwent a bilateral supraspinatus tenotomy that was repaired 30 days later. Rats were treated with SB203580 or vehicle every 2 days with injections beginning 3 days prior to surgery, and continued until 7 days after surgery. Two weeks after surgical repair muscles were analyzed using histology, lipid profiling, gene expression and permeabilized muscle fiber contractility. Results Inhibition of p38 MAPK resulted in a nearly 49% reduction in fat accumulation and a 29% reduction in collagen content, along with changes in corresponding genes regulating adipogenesis and matrix accumulation. There was also a marked 40–80% decrease in the expression of several proinflammatory genes, including IL1β, IL6 and COX2, and a 360% increase in the antiinflammatory gene IL10. No differences were observed for muscle fiber force production. Conclusion Inhibition of p38 MAPK was found to have a significant decrease in intramuscular lipid accumulation and fibrosis that is usually seen in the degenerative cascade of rotator cuff tears, without having negative effects on the contractile properties of the rotator cuff muscle tissue.

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

“…In addition to muscle atrophy, fibrosis is a common feature of rotator cuff tears (49)(50)(51). In the current study, 10 d after injury, there was an increase in the levels of the fibroblast marker S100A4 and several proteoglycans including lumican, osteoglycin, periostin, prolargin, thrombospondin 4, and vinculin.…”

Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis

“…Indeed, there are a number of well characterized pharmacologic inhibitors of p38 available, some of which have already shown the ability to broadly blunt fibrotic remodeling in mouse models of heart, lung and skeletal muscle disease 16, 17, 43-45 . While such agents are clearly attractive to consider in treating human cardiac fibrotic disease states, we also need to consider the timing of anti-fibrotic therapies so that the initial wound healing phase can be effectively maintained.…”

Transcriptomic Analysis of Cellular Pathways in Healing Flexor Tendons of Plasminogen Activator Inhibitor 1 (PAI‐1/Serpine1) Null Mice

“…The upregulation of PAI‐1 by TGF‐β1 has been reported to involve non‐canonical (smad‐independent) pathways such as MAPK activation of the transcription factor AP‐1 . Thus, the observed transcriptional inhibition of MAPK/ERK pathway could be correlated with reduced profibrotic processes during tendon healing previously reported in the PAI‐1 KO mice …”