title: Models of tibial fracture healing in normal and Nf1-deficient mice.
abstract: Delayed union and nonunion are common complications associated with tibial fractures, particularly in the distal tibia. Existing mouse tibial fracture models are typically closed and middiaphyseal, and thus poorly recapitulate the prevailing conditions following surgery on a human open distal tibial fracture. This report describes our development of two open tibial fracture models in the mouse, where the bone is broken either in the tibial midshaft (mid-diaphysis) or in the distal tibia. Fractures in the distal tibial model showed delayed repair compared to fractures in the tibial midshaft. These tibial fracture models were applied to both wild-type and Nf1-deficient (Nf1+/-) mice. Bone repair has been reported to be exceptionally problematic in human NF1 patients, and these patients can also spontaneously develop tibial nonunions (known as congenital pseudarthrosis of the tibia), which are recalcitrant to even vigorous intervention. pQCT analysis confirmed no fundamental differences in cortical or cancellous bone in Nf1-deficient mouse tibiae compared to wild-type mice. Although no difference in bone healing was seen in the tibial midshaft fracture model, the healing of distal tibial fractures was found to be impaired in Nf1+/- mice. The histological features associated with nonunited Nf1+/- fractures were variable, but included delayed cartilage removal, disproportionate fibrous invasion, insufficient new bone anabolism, and excessive catabolism. These findings imply that the pathology of tibial pseudarthrosis in human NF1 is complex and likely to be multifactorial.
authors.affiliation: Department of Orthopaedic Research & Biotechnology, Reasearch Building, Locked Bag 4001, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia. aarons@chw.edu.au
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
authors.forename: Alyson
authors.initials: A
authors.lastname: Morse
authors.forename: Lorraine
authors.initials: L
authors.lastname: Harry
authors.forename: Craig
authors.initials: C
authors.lastname: Godfrey
authors.forename: Kathy
authors.initials: K
authors.lastname: Mikulec
authors.forename: Michelle
authors.initials: M
authors.lastname: McDonald
authors.forename: Jürg A
authors.initials: JA
authors.lastname: Gasser
authors.forename: David G
authors.initials: DG
authors.lastname: Little
mesh_terms: D000818:Animals; D015519:Bone Density; D002146:Bony Callus / Q000473:pathology / Q000503:physiopathology; D002356:Cartilage / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D025542:Neurofibromin 1 / Q000235:genetics*; D010521:Periosteum / Q000473:pathology / Q000503:physiopathology; D011542:Pseudarthrosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D011859:Radiography; D013978:Tibial Fractures / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery
chemical_list: D025542:Neurofibromin 1