title: Fibroregulation of mesenchymal progenitor cells by BMP-4 after traumatic muscle injury.
abstract: OBJECTIVE
  Traumatized muscle is a complex healing environment containing cells with robust reparative and regenerative potential interacting in a cytokine milieu that influences the function and differentiation of these cells, leading to a spectrum of healing responses. In particular, bone morphogenetic protein-4 (BMP-4) is of interest as a potential modulator of healing because its dysregulation has been associated with fibrosis and heterotopic ossification formation. We propose a descriptive study of altered BMP-4 expression in traumatized muscle tissue and to evaluate its role in the fibroregulatory function of resident mesenchymal progenitor cells (MPCs) at the protein- and gene-expression levels.
  
  
  METHODS
  Protein-level expression of BMP-4 from cells resident in traumatized muscle specimens was evaluated using ELISA and also using sodium dodecyl sulfate-polyacrylamide gel electrophoresis to compare BMP-4 in homogenized muscle tissue specimens. BMP-4, cartilage oligomeric matrix protein (COMP), and osteocalcin expression localization was analyzed via immunohistochemistry. Reverse transcription-polymerase chain reaction was performed to evaluate fibroregulatory gene expression in MPCs after treatment with BMP-4.
  
  
  RESULTS
  BMP-4 was present in all traumatized muscle tissue specimens. Immunohistochemistry demonstrated that traumatized muscle fibers contained greater number of cells expressing BMP-4 in a more disorganized fashion compared with control samples. Reverse transcription-polymerase chain reaction demonstrated that COMP, growth and differentiation factor-10, and integrin beta-2 were up-regulated, whereas tumor necrosis factor-alpha was significantly down-regulated. COMP expression was colocalized in the traumatized muscle tissue with osteocalcin.
  
  
  CONCLUSIONS
  BMP-4 has an effect on MPCs that seems to promote fibrotic tissue formation. These findings suggest that BMP-4, while promoting osteoinduction, may also act on MPCs to promote formation of a fibrotic osteoinductive matrix. Thus, this signaling axis might be a potential target for heterotopic ossification prevention.
authors.affiliation: Clinical and Experimental Orthopaedics Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kluk
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Ji
authors.forename: Emily H
authors.initials: EH
authors.lastname: Shin
authors.forename: Orna
authors.initials: O
authors.lastname: Amrani
authors.forename: Jun
authors.initials: J
authors.lastname: Onodera
authors.forename: Wesley M
authors.initials: WM
authors.lastname: Jackson
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Nesti
mesh_terms: D001753:Blast Injuries / Q000378:metabolism* / Q000473:pathology*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4