1. Activation of BMP Signaling by FKBP12 Ligands Synergizes with Inhibition of CXCR4 to Accelerate Wound Healing
- Author
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Jun O. Liu, Hanjing Peng, Ali Reza Ahmadi, Le Qi, Yuefan Wang, Brandon J. Peiffer, Zufeng Guo, and Zhaoli Sun
- Subjects
Smad5 Protein ,Cell type ,Benzylamines ,Receptors, CXCR4 ,Clinical Biochemistry ,Tacrolimus Binding Protein 1A ,Biology ,Bone morphogenetic protein ,Cyclams ,Ligands ,01 natural sciences ,Biochemistry ,CXCR4 ,Peptides, Cyclic ,Article ,Tacrolimus ,Smad1 Protein ,Gene Knockout Techniques ,Jurkat Cells ,Heterocyclic Compounds ,Drug Discovery ,medicine ,polycyclic compounds ,Animals ,Humans ,Phosphorylation ,Molecular Biology ,Pharmacology ,Wound Healing ,integumentary system ,010405 organic chemistry ,organic chemicals ,Drug Synergism ,0104 chemical sciences ,Cell biology ,Rats ,Haematopoiesis ,Disease Models, Animal ,FKBP ,Mechanism of action ,Diabetes Mellitus, Type 2 ,Bone Morphogenetic Proteins ,cardiovascular system ,Molecular Medicine ,Female ,Stem cell ,medicine.symptom ,Wound healing ,Signal Transduction - Abstract
Summary 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.
- Published
- 2018