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Activation of hedgehog signaling by systemic agonist improves fracture healing in aged mice
Author(s) -
McKenzie Jennifer A.,
Maschhoff Clayton,
Liu Xiaochen,
Migotsky Nicole,
Silva Matthew J.,
Gardner Michael J.
Publication year - 2019
Publication title -
journal of orthopaedic research®
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.24017
Subject(s) - agonist , bone healing , smoothened , hedgehog signaling pathway , endocrinology , callus , medicine , chemistry , sonic hedgehog , cyclopamine , signal transduction , receptor , surgery , biology , biochemistry , genetics
Fracture healing is a complex process of many coordinated biological pathways. This system can go awry resulting in nonunion, which leads to significant patient morbidity. The Hedgehog (Hh) signaling pathway is upregulated in fracture healing. We hypothesized that the Hh signaling pathway can be pharmacologically modulated to positively affect fracture healing. Diaphyseal femur fractures were created in elderly mice (18 months, C57BL/6 females), which have a blunted and delayed healing response compared to younger mice, and were stabilized with intramedullary pins. To activate the Hh pathway we targeted the receptor Smoothened using an agonist (Hh‐Ag1.5 [Hh‐Ag]) and compared this to a vehicle control. Expression of Hh target genes were significantly increased in the fracture callus of the agonist group compared to controls, indicating pathway activation. Expression of osteogenic and chondrogenic‐related genes was greatly upregulated in fracture callus versus intact femora, although Hh agonist treatment did not consistently enhance this response. Blindly graded, radiographic callus healing scores were significantly higher in the Hh‐Ag groups at post operative day (POD) 14, indicating earlier callus bridging. On microCT, Hh‐Ag treatment led to greater callus volume (+40%) and bone volume (+25%) at POD21. By day 14, callus vascularity, as assessed by 3D microCT angiography vessel volume, was 85% greater in the Hh‐Ag group. Finally, mechanical strength of the calluses in the Hh‐Ag groups was significantly greater than in the control groups at POD21. In conclusion, systemic administration of a Hh agonist appears to improve the osseous and vascular healing responses in a mouse fracture healing‐impaired model. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res