Fibroregulation of mesenchymal progenitor cells by BMP-4 after traumatic muscle injury

Matthew W. Kluk, Youngmi Ji, Emily H. Shin, Orna Amrani, Jun Onodera, Wesley M. Jackson, Leon J. Nesti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


OBJECTIVES: 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.

Original languageEnglish
Pages (from-to)693-698
Number of pages6
JournalJournal of Orthopaedic Trauma
Issue number12
StatePublished - Dec 2012
Externally publishedYes


  • fibrosis
  • heterotopic ossification
  • mesenchymal stem cells
  • polytrauma


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