Local administration of a hedgehog agonist accelerates fracture healing in a mouse model.
Bone fracture healing is processed through multiple biological stages including the transition from cartilaginous callus to bony callus formation. Because of its specific, temporal and indispensable functions demonstrated by mouse genetic studies, Hedgehog (Hh) signaling is one of the most potent signaling pathways involved in these processes, but the effect of Hh-signaling activation by small compounds on the repair process had not yet been addressed. Here we examined therapeutic effects of local and one shot-administration of the Hh agonist known as smoothened agonist (SAG) on bone fracture healing in a mouse model. A quantitative analysis with three-dimensional micro-computed tomography showed that SAG administration increased the size of both the cartilaginous callus and bony callus at 14 days after the surgery. A histological analysis showed that SAG administration increased the number of cells expressing a proliferation marker and a chondrocyte marker in cartilaginous callus as well as the cells expressing an osteoblast marker in bony callus. These results indicate that the SAG administration resulted in an enhancement of callus formation during bone fracture healing, which is at least in part mediated by an increase in chondrocyte proliferation in cartilaginous callus and the promotion of bone formation in bony callus. Therapeutic strategies with a SAG-mediated protocol may thus be useful for the treatment of bone fractures.
Department of Sensory and Motor System Medicine, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033, Japan; Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033, Japan.
Miki
M
Kashiwagi
Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, 113-8656, Japan.
Hironori
H
Hojo
Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033, Japan; Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, 113-8656, Japan.
Yoshiaki
Y
Kitaura
Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, 113-8656, Japan.
Yujiro
Y
Maeda
Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, 113-8656, Japan.
Hailati
H
Aini
Department of Sensory and Motor System Medicine, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033, Japan.
Tsuyoshi
T
Takato
Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033, Japan; Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, 113-8656, Japan.
Ung-Il
UI
Chung
Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033, Japan; Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, 113-8656, Japan. Electronic address: ohba@bioeng.t.u-tokyo.ac.jp.
Shinsuke
S
Ohba
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002146:Bony Callus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D003514:Cyclohexylamines / Q000008:administration & dosage*; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D053823:Hedgehog Proteins / Q000819:agonists*; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013876:Thiophenes / Q000008:administration & dosage*; D013978:Tibial Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D055114:X-Ray Microtomography
D003514:Cyclohexylamines; D053823:Hedgehog Proteins; C468918:SAG compound; D013876:Thiophenes
Bone fracture healing; Callus formation; Chondrocyte; Hedgehog; Osteoblast; Smoothened agonist