title: Sensory nerve induced inflammation contributes to heterotopic ossification.
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.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Salisbury
authors.forename: Eric
authors.initials: E
authors.lastname: Rodenberg
authors.forename: Corinne
authors.initials: C
authors.lastname: Sonnet
authors.forename: John
authors.initials: J
authors.lastname: Hipp
authors.forename: Francis H
authors.initials: FH
authors.lastname: Gannon
authors.forename: Tegy J
authors.initials: TJ
authors.lastname: Vadakkan
authors.forename: Mary E
authors.initials: ME
authors.lastname: Dickinson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Olmsted-Davis
authors.forename: Alan R
authors.initials: AR
authors.lastname: Davis
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002460:Cell Line; D004205:Cromolyn Sodium / Q000494:pharmacology; D007150:Immunohistochemistry; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008810:Mice, Inbred C57BL; D020078:Neurogenic Inflammation / Q000150:complications* / Q000503:physiopathology*; D009999:Ossification, Heterotopic / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000276:immunology / Q000473:pathology*; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D055396:Bone Morphogenetic Protein 2; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D004205:Cromolyn Sodium