Sensory nerve induced inflammation contributes to heterotopic ossification

Elizabeth Salisbury, Eric Rodenberg, Corinne Sonnet, John Hipp, Francis H. Gannon, Tegy J. Vadakkan, Mary E. Dickinson, Elizabeth A. Olmsted-Davis, Alan R. Davis

Research output: Contribution to journalArticle

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Abstract

Heterotopic ossification (HO), or bone formation in soft tissues, is often the result of traumatic injury. Much evidence has linked the release of BMPs (bone morphogenetic proteins) upon injury to this process. HO was once thought to be a rare occurrence, but recent statistics from the military suggest that as many as 60% of traumatic injuries, resulting from bomb blasts, have associated HO. In this study, we attempt to define the role of peripheral nerves in this process. Since BMP2 has been shown previously to induce release of the neuroinflammatory molecules, substance P (SP) and calcitonin gene related peptide (CGRP), from peripheral, sensory neurons, we examined this process in vivo. SP and CGRP are rapidly expressed upon delivery of BMP2 and remain elevated throughout bone formation. In animals lacking functional sensory neurons (TRPV1 -/-), BMP2-mediated increases in SP and CGRP were suppressed as compared to the normal animals, and HO was dramatically inhibited in these deficient mice, suggesting that neuroinflammation plays a functional role. Mast cells, known to be recruited by SP and CGRP, were elevated after BMP2 induction. These mast cells were localized to the nerve structures and underwent degranulation. When degranulation was inhibited using cromolyn, HO was again reduced significantly. Immunohistochemical analysis revealed nerves expressing the stem cell markers nanog and Klf4, as well as the osteoblast marker osterix, after BMP2 induction, in mice treated with cromolyn. The data collectively suggest that BMP2 can act directly on sensory neurons to induce neurogenic inflammation, resulting in nerve remodeling and the migration/release of osteogenic and other stem cells from the nerve. Further, blocking this process significantly reduces HO, suggesting that the stem cell population contributes to bone formation.

Original languageEnglish (US)
Pages (from-to)2748-2758
Number of pages11
JournalJournal of Cellular Biochemistry
Volume112
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

Fingerprint

Heterotopic Ossification
Calcitonin Gene-Related Peptide
Substance P
Stem cells
Neurons
Inflammation
Cromolyn Sodium
Bone
Sensory Receptor Cells
Osteogenesis
Animals
Stem Cells
Mast Cells
Bone Morphogenetic Proteins
Osteoblasts
Wounds and Injuries
Neurogenic Inflammation
Bombs
Statistics
Tissue

Keywords

  • bone morphogenetic protein type 2
  • heterotopic ossification
  • neural crest stem cells
  • neurogenic inflammation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Salisbury, E., Rodenberg, E., Sonnet, C., Hipp, J., Gannon, F. H., Vadakkan, T. J., ... Davis, A. R. (2011). Sensory nerve induced inflammation contributes to heterotopic ossification. Journal of Cellular Biochemistry, 112(10), 2748-2758. https://doi.org/10.1002/jcb.23225

Sensory nerve induced inflammation contributes to heterotopic ossification. / Salisbury, Elizabeth; Rodenberg, Eric; Sonnet, Corinne; Hipp, John; Gannon, Francis H.; Vadakkan, Tegy J.; Dickinson, Mary E.; Olmsted-Davis, Elizabeth A.; Davis, Alan R.

In: Journal of Cellular Biochemistry, Vol. 112, No. 10, 10.2011, p. 2748-2758.

Research output: Contribution to journalArticle

Salisbury, E, Rodenberg, E, Sonnet, C, Hipp, J, Gannon, FH, Vadakkan, TJ, Dickinson, ME, Olmsted-Davis, EA & Davis, AR 2011, 'Sensory nerve induced inflammation contributes to heterotopic ossification', Journal of Cellular Biochemistry, vol. 112, no. 10, pp. 2748-2758. https://doi.org/10.1002/jcb.23225
Salisbury, Elizabeth ; Rodenberg, Eric ; Sonnet, Corinne ; Hipp, John ; Gannon, Francis H. ; Vadakkan, Tegy J. ; Dickinson, Mary E. ; Olmsted-Davis, Elizabeth A. ; Davis, Alan R. / Sensory nerve induced inflammation contributes to heterotopic ossification. In: Journal of Cellular Biochemistry. 2011 ; Vol. 112, No. 10. pp. 2748-2758.
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