TY - JOUR
T1 - Healing of non-displaced fractures produced by fatigue loading of the mouse ulna
AU - Martinez, Mario D.
AU - Schmid, Gregory J.
AU - McKenzie, Jennifer A.
AU - Ornitz, David M.
AU - Silva, Matthew J.
N1 - Funding Information:
This study was supported by grants from the NIH ( R01AR050211 , R01HD049808 , P30AR057235 ) and the ASBMR . We thank C. Smith for technical assistance.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - FGF signaling
KW - Fatigue loading
KW - Fracture healing
KW - Hypoxia
KW - Mouse ulna
KW - Woven bone
UR - http://www.scopus.com/inward/record.url?scp=77953028993&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2010.02.030
DO - 10.1016/j.bone.2010.02.030
M3 - Article
C2 - 20215063
AN - SCOPUS:77953028993
SN - 8756-3282
VL - 46
SP - 1604
EP - 1612
JO - Bone
JF - Bone
IS - 6
ER -