Healing of non-displaced fractures produced by fatigue loading of the mouse ulna

Mario D. Martinez, Gregory J. Schmid, Jennifer A. McKenzie, David M. Ornitz, Matthew J. Silva

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

We developed a fatigue loading protocol in mice to produce a non-displaced ulnar fracture in vivo, and characterized the early healing response. Using adult (5. month) C57Bl/6 mice, we first determined that cyclic compression of the forelimb under load-control leads to increasing applied displacement and, eventually, complete fracture. We then subjected the right forelimbs of 80 mice to cyclic loading (2. Hz; peak force ~. 4. N) and limited the displacement increase to 0.75. mm (60% of the average displacement increase at complete fracture). This fatigue protocol created a partial, non-displaced fracture through the medial cortex near the ulnar mid-shaft, and reduced ulnar strength and stiffness by > 50%. Within 1. day, there was significant upregulation of genes related to hypoxia (Hif1a) and osteogenesis (Bmp2, Bsp) in loaded ulnae compared to non-loaded, contralateral controls. The gene expression response peaked in magnitude near day 7 (e.g., Osx upregulated 8-fold), and included upregulation of FGF-family genes (e.g., Fgfr3 up 6-fold). Histologically, a localized periosteal response was seen at the site of the fracture; by day 7 there was abundant periosteal woven bone surrounding a region of cartilage. From days 7 to 14, the woven bone became denser but did not increase in area. By day 14, the woven-bone response resulted in complete recovery of ulnar strength and stiffness, restoring mechanical properties to normal levels. In the future, the fatigue loading approach can be used create non-displaced bone fractures in transgenic and knockout mice to study the mechanisms by which the skeleton rapidly repairs damage.

Original languageEnglish
Pages (from-to)1604-1612
Number of pages9
JournalBone
Volume46
Issue number6
DOIs
StatePublished - Jun 1 2010

Keywords

  • FGF signaling
  • Fatigue loading
  • Fracture healing
  • Hypoxia
  • Mouse ulna
  • Woven bone

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