title: Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice.
abstract: Skeletal trauma and impaired skeletal healing is commonly associated with diminished vascularity. Hypoxia inducible factor alpha (HIF-1) is a key transcription factor responsible for activating angiogenic factors during development and tissue repair. Small molecule inhibitors of the prolyl hydroxylase enzyme (PHD), the key enzyme responsible for degrading HIF-1, have been shown to activate HIF-1, and are effective in inducing angiogenesis. Here we examined the effects of several commercially available PHD inhibitors on bone marrow mesenchymal stromal cells (MSCs) in vitro and in a stabilized fracture model in vivo. Three PHD inhibitors [Desferrioxamine (DFO), L-mimosine (L-mim), and Dimethyloxalylglycine (DMOG)] effectively activated a HIF-1 target reporter, induced expression of vascular endothelial growth factor (VEGF) mRNA in vitro, and increased capillary sprouting in a functional angiogenesis assay. DFO and DMOG were applied by direct injection at the fracture site in a stabilized murine femur fracture model. PHD inhibition increased the vascularity at 14 days and increased callus size as assessed by microCT at 28 days. These results suggest that HIF activation is a viable approach to increase vascularity and bone formation following skeletal trauma.
authors.affiliation: Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Jiao Tong University, School of Medicine, Shanghai, People's Republic of China.
authors.forename: Xing
authors.initials: X
authors.lastname: Shen
authors.forename: Chao
authors.initials: C
authors.lastname: Wan
authors.forename: Girish
authors.initials: G
authors.lastname: Ramaswamy
authors.forename: Mahendra
authors.initials: M
authors.lastname: Mavalli
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Craig L
authors.initials: CL
authors.lastname: Duvall
authors.forename: Lian Fu
authors.initials: LF
authors.lastname: Deng
authors.forename: Robert E
authors.initials: RE
authors.lastname: Guldberg
authors.forename: Alan
authors.initials: A
authors.lastname: Eberhart
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Gilbert