Activation of BMP Signaling by FKBP12 Ligands Synergizes with Inhibition of CXCR4 to Accelerate Wound Healing

Cell Chem Biol. 2019 May 16;26(5):652-661.e4. doi: 10.1016/j.chembiol.2019.01.011. Epub 2019 Feb 28.

Abstract

The combination of AMD3100 and low-dose FK506 has been shown to accelerate wound healing in vivo. Although AMD3100 is known to work by releasing hematopoietic stem cells into circulation, the mechanism of FK506 in this setting has remained unknown. In this study, we investigated the activities of FK506 in human cells and a diabetic-rat wound model using a non-immunosuppressive FK506 analog named FKVP. While FKVP was incapable of inhibiting calcineurin, wound-healing enhancement with AMD3100 was unaffected. Further study showed that both FK506 and FKVP activate BMP signaling in multiple cell types through FKBP12 antagonism. Furthermore, selective inhibition of BMP signaling abolished stem cell recruitment and wound-healing enhancement by combination treatment. These results shed new light on the mechanism of action of FK506 in acceleration of wound healing, and raise the possibility that less toxic FKBP ligands such as FKVP can replace FK506 for the treatment of chronic wounds.

Keywords: AMD3100; FK506; FKBP; bone morphogenic protein; stem cells; wound healing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzylamines
  • Bone Morphogenetic Proteins / metabolism
  • Cyclams
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Gene Knockout Techniques
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Jurkat Cells
  • Ligands*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Phosphorylation / drug effects
  • Rats
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction / drug effects*
  • Smad1 Protein / metabolism
  • Smad5 Protein / metabolism
  • Tacrolimus / chemistry
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Protein 1A / chemistry*
  • Tacrolimus Binding Protein 1A / deficiency
  • Tacrolimus Binding Protein 1A / genetics
  • Tacrolimus Binding Protein 1A / metabolism
  • Wound Healing / drug effects*

Substances

  • Benzylamines
  • Bone Morphogenetic Proteins
  • Cyclams
  • Heterocyclic Compounds
  • Ligands
  • Peptides, Cyclic
  • Receptors, CXCR4
  • Smad1 Protein
  • Smad5 Protein
  • Tacrolimus Binding Protein 1A
  • plerixafor
  • Tacrolimus