Activation of BMP Signaling by FKBP12 Ligands Synergizes with Inhibition of CXCR4 to Accelerate Wound Healing. Issue 5 (16th May 2019)

• Record Type: Journal Article
• Authors: Peiffer, Brandon J.; Qi, Le; Ahmadi, Ali R.; Wang, Yuefan; Guo, Zufeng; Peng, Hanjing; Sun, Zhaoli; Liu, Jun O.
• Is Part Of: Cell chemical biology. Volume 26:Issue 5(2019)
• Page Start: 652
• Page End: 661.e4
• Publication Date: 2019-05-16
• Subjects: wound healing -- stem cells -- bone morphogenic protein -- FKBP -- FK506 -- AMD3100; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.01.011
• Languages: English
• ISSNs: 2451-9456

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. Graphical Abstract: Highlights: Accelerated wound healing promoted by FK506 is independent of calcineurin inhibition A non-immunosuppressive FK506 analog activates BMP pathway signaling in human cells Blockade of BMP signaling abolishes acceleration of healing by combination treatment BMP receptor inhibition prevents stem cell recruitment at wound sites in vivo Abstract : Peiffer and colleagues report that a non-immunosuppressive FK506 analog (FKVP) significantly accelerates wound healing in diabetic rats when combined with AMD3100. FKVP was found to exert this FKBP12-specific effect through activation of the BMP pathway. Conversely, systemic BMP inhibition blocked treatment-enhanced healing and stem cell recruitment at wound areas.