Abstract
Biodegradable magnesium (Mg) implant generally provides temporary fracture fixation and facilitates bone regeneration. However, the exact effects of generated Mg ions (Mg2+), hydrogen gas (H2), and hydroxide ions (OH-) by Mg degradation on enhancing fracture healing are not fully understood. Here we investigate the in vivo degradation of Mg intramedullary nail (Mg-IMN), revealing the generation of these degradation products around the fracture site during early stages. Bulk-RNA seq indicates that H2 and alkaline pH increase periosteal cell proliferation, while Mg2+ may mainly enhance extracellular matrix formation and cell adhesion in the femur ex vivo. In vivo studies further reveal that H2, Mg2+ and alkaline pH individually generate comparable effects to the enhanced bone regeneration in the Mg-IMN group. Mechanistically, the degradation products elevate sensory calcitonin gene-related peptide (CGRP) and simultaneously suppress adrenergic factors in newly formed bone. H2 and Mg2+, instead of alkaline pH, increase CGRP synthesis and inhibit adrenergic receptors. Our findings, for the first time, elucidate that Mg2+, H2, and alkaline pH environment generated by Mg-IMN act distinctly and synergistically mediated by the skeletal interoceptive regulation to accelerate bone regeneration. These findings may advance the understanding on biological functions of Mg-IMN in fracture repair and even other bone disorders.