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

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. A signaling molecule that plays a central role in these processes is p38 mitogen-activated protein kinase (MAPK). The purpose of this study was to evaluate the ability of a small molecule inhibitor of p38 MAPK, SB203580, to reduce fatty degeneration in a preclinical model of rotator cuff injury and repair. MATERIALS AND 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 before surgery and continuing 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% to 80% decrease in the expression of several proinflammatory genes, including IL1B, IL6, and COX2, and a 360% increase in the anti-inflammatory gene IL10. No differences were observed for muscle fiber force production. CONCLUSION: Inhibition of p38 MAPK was found to result in 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.

Synergist ablation induces rapid tendon growth through the synthesis of a neotendon matrix.

Mechanical loading can increase tendon cross-sectional area (CSA), but the mechanisms by which this occurs are largely unknown. To gain a greater understanding of the cellular mechanisms of adult tendon growth in response to mechanical loading, we used a synergist ablation model whereby a tenectomy of the Achilles tendon was performed to induce growth of the synergist plantaris tendon. We hypothesized that after synergist ablation progenitor cells in the epitenon would proliferate and increase the size of the existing tendon matrix. Adult male mice were subjected to a bilateral Achilles tenectomy, and plantaris tendons were isolated from mice at 0, 2, 7, 14, and 28 days after surgery. Tendons were sectioned stained with either fast green and hematoxylin, prepared for fluorescent microscopy, or prepared for gene expression of scleraxis and type I collagen. After overload, there was a dramatic increase in total CSA of tendons, whereas the size of the original tendon matrix was not changed. Growth primarily occurred through the formation of a neotendon matrix between the original tendon and the epitenon, and contained cells that were proliferative and scleraxis positive. Additionally, an initial expansion of fibroblast cells occurred before the synthesis of new extracellular matrix. Fibroblasts in the original tendon did not re-enter the cell cycle. The results from this study provide new insight into the mechanisms of tendon growth, indicate tendon consists mostly of postmitotic cells, and that growth of tendon primarily occurs from the most superficial layers outward.