title: 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. 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Wilde
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Gumucio
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Grekin
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Dylan C
authors.initials: DC
authors.lastname: Sarver
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Noah
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Ruehlmann
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Max E
authors.initials: ME
authors.lastname: Davis
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Asheesh
authors.initials: A
authors.lastname: Bedi
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: cmendias@umich.edu.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Mendias
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D023421:Models, Animal; D011725:Pyridines / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017006:Rotator Cuff / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C000594089:IL1B protein, rat; D007093:Imidazoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D011725:Pyridines; D016753:Interleukin-10; D012313:RNA; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Fatty degeneration; atrophy; fibrosis; inflammation; myosteatosis; p38 MAPK; rotator cuff