Magnesium supplementation reduces cigarette smoke–associated cell damage in 3D bone fracture healing model

Abstract

It is well established that CS has an adverse impact on bone homeostasis, contributing to increased risk of fragility fractures and impaired fracture healing. CS is capable of suppressing osteoblast function and improving osteoclast function. Mg is engaged in promoting osteogenic differentiation of osteoblast progenitor cells and suppressing osteoclastic differentiation of osteoclast progenitor cells. Not surprisingly, Mg deficiency has been associated with bone loss. Interestingly, a clinical study reported that heavy smokers had a remarkably lower serum Mg level compared to nonsmokers. Based on this finding, we hypothesized that Mg supplementation is capable of reversing the adverse impacts of CS on bone metabolism. In this study, we constructed an in vitro bone co-culture system containing SCP-1 cells and THP-1 cells co-cultured on a scaffold, mimicking the reparative phase of bone fracture healing in vivo as closely as possible. Then, we investigated the impact of Mg supplementation on the 3D bone co-culture system impaired by CSE. We observed that 5% CSE is capable of enhancing osteoclastic differentiation and inhibiting osteogenic differentiation in the 3D bone co-culture system, creating an osteoporotic microenvironment as observed in the smokers with osteoporotic bones. Supplementation with 4 mM Mg effectively inhibited osteoclast function (TRAP and CAII activity) and enhanced matrix mineralization (PINP and OCN levels) in CSE-induced bone cells by switching to upregulation of OPG. Furthermore, the protective effects of Mg supplementation were more pronounced at 4 mM than at 1 mM. Based on these findings, Mg supplementation may be an effective strategy to prevent or treat osteoporotic bones in smokers. When patients are found to have Mg deficiency, Mg supplementation can be administered orally or intravenously to prevent or treat osteoporotic bones, especially for smokers. Further clinical studies are required to clarify the Mg administration patterns, such as dose and duration.