Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing

Bone
Nikolas H KazmersMatthew J Silva

Abstract

Hedgehog (Hh) signaling is critical in developmental osteogenesis, and recent studies suggest it may also play a role in regulating osteogenic gene expression in the post-natal setting. However, there is a void of studies directly assessing the effect of Hh inhibition on post-natal osteogenesis. This study utilized a cyclic loading-induced ulnar stress fracture model to evaluate the hypothesis that Hh signaling contributes to osteogenesis and angiogenesis during stress fracture healing. Immediately prior to loading, adult rats were given GDC-0449 (Vismodegib - a selective Hh pathway inhibitor; 50mg/kg orally twice daily), or vehicle. Hh signaling was upregulated in response to stress fracture at 3 days (Ptch1, Gli1 expression), and was markedly inhibited by GDC-0449 at 1 day and 3 days in the loaded and non-loaded ulnae. GDC-0449 did not affect Hh ligand expression (Shh, Ihh, Dhh) at 1 day, but decreased Shh expression by 37% at 3 days. GDC-0449 decreased woven bone volume (-37%) and mineral density (-17%) at 7 days. Dynamic histomorphometry revealed that the 7 day callus was composed predominantly of woven bone in both groups. The observed reduction in woven bone occurred concomitantly with decreased expression of Alpl and Ibs...Continue Reading

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Citations

Jun 28, 2016·Biomaterials·Alexandra Lisovsky, Michael V Sefton
Oct 4, 2016·Biochemical and Biophysical Research Communications·Miki KashiwagiShinsuke Ohba
Aug 26, 2018·Clinical and Experimental Pharmacology & Physiology·Paweł ŁęgoszPaweł Małdyk
Apr 18, 2018·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Jennifer A McKenzieMichael J Gardner
Nov 21, 2019·Cell Proliferation·Shaoling YuLili Chen
Apr 16, 2020·Journal of Cellular and Molecular Medicine·Qiang ZhangJun Tan
Jan 13, 2019·Stem Cell Research & Therapy·Chen KanLixin Kan
Apr 1, 2020·Advances in Wound Care·Bei-Bei YangXiao-Yong Man
Aug 21, 2019·International Journal of Molecular Sciences·Wen-Ting LvChun-Jie Wang
Jun 5, 2017·Molecular and Cellular Biochemistry·Celio J da Costa FernandesWillian F Zambuzzi

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