Elucidation of the mechanism of human growth hormone-Fc fusion protein in accelerating tibial fracture healing in rats via untargeted metabolomics

Abstract

BACKGROUND: Fracture healing has always been a major challenge in clinical practice. This study aims to explore the effect of human growth hormone-Fc fusion protein on the healing of a rat tibial fracture model and its possible mechanisms of action. METHODS: By assessing the levels of growth hormone effectors IGF-1 and IGFBP-3 in rats, combined with Micro-CT scanning and pathological staining slices, we investigated the pathological effects of subcutaneous injection of human growth hormone-Fc fusion protein for 28 days on the healing of rat tibial fractures. Serum metabolomics studies were conducted using the AB Triple TOF 6600 mass spectrometer to further investigate the bio-metabolites relevant to fracture healing influenced by the human growth hormone-Fc fusion protein. RESULTS: The study showed that after administration of the growth hormone-Fc fusion protein, IGF-1 and IGFBP-3 levels in rat blood were significantly increased. Micro-CT scans and pathological staining also demonstrated that the high-dose group had a marked promoting effect on fracture healing, with a healing rate significantly superior to the positive drug group; the medium and low dose groups also showed certain degrees of promotion. Metabolomic results revealed that the growth hormone could regulate 17 metabolites, affecting 8 metabolic pathways in relation to fracture healing. CONCLUSION: The study found that the growth hormone-Fc fusion protein shortened the healing period of the rat tibial fracture model by more than 1 week, possibly by influencing the levels of IGF-1 and IGFBP-3 factors, as well as regulating 17 metabolites in 8 metabolic pathways-including starch and sucrose metabolism, galactose metabolism, glycerophospholipid metabolism, terpene backbone biosynthesis, glyoxylate and dicarboxylate metabolism, retinol metabolism, glycine, serine, and threonine metabolism, and inositol phosphate metabolism-thus promoting fracture healing. This provides a basis for subsequent larger-scale, multicenter experiments and clinical translational research on FcGH in the treatment of fractures.

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