CGRP promotes osteogenic differentiation by regulating macrophage M2 polarization through HDAC6/AKAP12 signaling pathway.

Aim: To determine the mechanism of Calcitonin gene-related peptide (CGRP) in bone healing. Materials & methods: Alkaline phosphatase (ALP) activity and inflammatory-factor levels were detected using ELISA. Osteogenic differentiation was assessed using Alizarin red staining technique. The interaction between histone deacetylase 6 (HDAC6) and A-kinase anchoring protein 12 (AKAP12) was investigated through Co- immunoprecipitation. Results: CGRP treatment promoted rat bone marrow-derived macrophages (BMDMs) M2 polarization. CGRP facilitated osteogenic differentiation by enhancing M2 polarization of BMDMs. Mechanistically, CGRP promoted AKAP12 acetylation to activate the extracellular regulated protein kinases pathway by HDAC6 inhibition. Conclusion: CGRP promoted M2 polarization of rat BMDMs and facilitated osteogenic differentiation through the HDAC6/AKAP12/extracellular regulated protein kinases signaling pathway, thereby promoting bone healing. Graphical Abstract Article highlights Diverse concentrations of calcitonin gene-related peptide (CGRP) induced M2 polarization in rat macrophages. CGRP promoted osteogenic differentiation after co-culture of rat macrophages and rat osteoblasts. With the increase in CGRP concentration, there was a gradual downregulation of histone deacetylase 6 expression. CGRP promoted M2 polarization of rat bone marrow-derived macrophages and facilitated osteogenic differentiation through histone deacetylase 6/A-kinase anchoring protein 12/extracellular regulated protein kinases signaling pathway, thereby promoting bone healing. The present findings offer a theoretical basis for clinical interventions in fracture healing. [ABSTRACT FROM AUTHOR]