Agonistic analogs of growth hormone releasing hormone (GHRH) promote wound healing by stimulating the proliferation and survival of human dermal fibroblasts through ERK and AKT pathways

// Tengjiao Cui 1,2,7 , Joaquin J. Jimenez 4,5 , Norman L. Block 3 , Evangelos V. Badiavas 4,8 , Luis Rodriguez-Menocal 4,8 , Ailin Vila Granda 4 , Renzhi Cai 1,2,7 , Wei Sha 1,2,8 , Marta Zarandi 1,2 , Roberto Perez 1,2 and Andrew V. Schally 1,2,3,6,7,8,9 1 Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA 2 South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL, USA 3 Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA 4 Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA 5 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA 6 Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA 7 Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA 8 Department of Medicine, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA 9 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA Correspondence: Andrew V. Schally, email: // Keywords : GHRH agonists, human dermal fibroblast, wound healing, ERK pathway, AKT pathway, Pathology Section Received : July 06, 2016 Accepted : July 23, 2016 Published : August 02, 2016 Abstract Decreased or impaired proliferation capability of dermal fibroblasts interferes with successful wound healing. Several growth factors tested failed to fully restore the growth of fibroblasts, possibly due to their rapid degradation by proteases. It is therefore critical to find new agents which have stimulatory effects on fibroblasts while being highly resistant to degradation. In such a scenario, the activities of two agonistic analogs of growth hormone releasing hormone (GHRH), MR-409 and MR-502, were evaluated for their impact on proliferation and survival of primary human dermal fibroblasts. In vitro , both analogs significantly stimulated cell growth by more than 50%. Under serum-depletion induced stress, fibroblasts treated with MR-409 or MR-502 demonstrated better survival rates than control. These effects can be inhibited by either PD98059 or wortmannin. Signaling through MEK/ERK1/2 and PI3K/AKT in an IGF-1 receptor-independent manner is required. In vivo , MR-409 promoted wound closure. Animals treated topically with MR-409 healed earlier than controls in a dose-dependent manner. Histologic examination revealed better wound contraction and less fibrosis in treated groups. In conclusion, MR-409 is a potent mitogenic and anti-apoptotic factor for primary human dermal fibroblasts. Its beneficial effects on wound healing make it a promising agent for future development.