title: Location-dependent heterotopic ossification in the rat model: The role of activated matrix metalloproteinase 9.
abstract: Extremity amputation or traumatic injury can often lead to the formation of heterotopic ossification (HO). Studies to induce HO in rat muscle using cell-based gene therapy show that this process appears to be location dependent. In the present study, HO was induced in mice and rats through injection of immunologically matched cells transduced with either a replication-defective adenovirus possessing bone morphogenetic protein 2 (BMP2) or an empty adenovirus vector (control). Injection in rat near the skeletal bone resulted in HO, whereas cells injected into the same muscle group but distal from the bone did not result in bone formation. When cells were injected in the same limb at both locations at the same time, HO was formed at both sites. Characterization of the bone formation in rats versus mice demonstrated that different sources of osteogenic progenitors were involved, which may account for the location dependent bone formation observed in the rat. Further experimentation has shown that a potential reason for this difference may be the inability of rat to activate matrix metalloproteinase 9 (MMP9), an essential protease in mice necessary for recruitment of progenitors. Inhibition of active MMP9 in mice led to a significant decrease in HO. The studies reported here provide insight into the mechanisms and pathways leading to bone formation in different animals and species. It appears that not all animal models are appropriate for testing HO therapies, and our studies also challenge the conventional wisdom that larger animal models are better for testing treatments affecting bone. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1894-1904, 2016.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Eleanor L
authors.initials: EL
authors.lastname: Davis
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 77030.|Department of Medicine, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Corinne
authors.initials: C
authors.lastname: Sonnet
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: ZaWaunyka W
authors.initials: ZW
authors.lastname: Lazard
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Henslee
authors.affiliation: Department of Orthopedic Surgery, University of Texas Medical Branch Galveston, Galveston, Texas, 77555.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Gugala
authors.affiliation: Department of Orthopedic Surgery, University of Texas Medical Branch Galveston, Galveston, Texas, 77555.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Salisbury
authors.affiliation: Department of Orthopedic Surgery, University of Texas Medical Branch Galveston, Galveston, Texas, 77555.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Strecker
authors.affiliation: Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, Maryland, 20910.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
authors.affiliation: Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, Maryland, 20910.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Forsberg
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 77030.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030.|Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Davis
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 77030.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030.|Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Olmsted-Davis
mesh_terms: D000256:Adenoviridae; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D045164:Mesenchymal Stem Cell Transplantation; D008810:Mice, Inbred C57BL; D009999:Ossification, Heterotopic; D011923:Rats, Nude; D017208:Rats, Wistar
chemical_list: D020780:Matrix Metalloproteinase 9
keywords: BMP2; Heterotopic ossification; matrix metalloproteinase-9