High Fluoride Ingestion Impairs Bone Fracture Healing by Attenuating M2 Macrophage Differentiation

Abstract

Fluorosis is still endemic in at least 25 countries around the world. In this study, we investigated the effect of high fluoride intake on fracture healing. Our in vitro experiments found that fluoride inhibited the osteogenic and angiogenic differentiation of MSCs in a dose-dependent manner. By constructing a bone fracture model, we found that high fluoride intake influences bone fracture by attenuating endochondral ossification and angiogenesis. In the mechanism, we clarified that high fluoride inhibits M2 differentiation rather than M1 differentiation in the fracture area, which may contribute to the delayed healing of the fracture. These findings provide an essential reference for the clinical treatment of bone fracture patients with a history of high fluoride intake or skeletal fluorosis patients.

The role of macrophages in fracture healing: a narrative review of the recent updates and therapeutic perspectives

“…In a rat fracture healing model, Du et al found that the number of CD86 + M1 macrophages increased at the fracture site on day 7 after the fracture, while the number of CD206 + M2 macrophages decreased. At 21 days, the number of M1 macrophages was still high in the fluoride treated group, indicating that fluoride results in prolongation of the pro-inflammatory stage, and therefore inhibition of the tissue neoformation phase (64).…”

Reduced angiogenesis and delayed endochondral ossification in CD163−/− mice highlights a role of M2 macrophages during bone fracture repair

“…7,8 More specifically, M2 macrophages have been implicated in murine models of osteoporotic fracture healing, [9][10][11] and high fluoride ingestion was shown to impair fracture healing by attenuating M2 macrophage differentiation. 12 Thus, modulating macrophage polarization for the enhancement of fracture healing has been recognized to be a therapeutic target, and the subject has been systemically reviewed. 13 Some of these M2 macrophage polarizing treatments, including interleukin 4 and 13 (IL-4 and IL-13), vibration, 14 trehalose, 15 and nanoparticles magnetically delivered to the fracture site.…”

“…Preclinical functional studies have shown that depletion of macrophages negatively affects bone fracture healing 7,8 . More specifically, M2 macrophages have been implicated in murine models of osteoporotic fracture healing, 9–11 and high fluoride ingestion was shown to impair fracture healing by attenuating M2 macrophage differentiation 12 . Thus, modulating macrophage polarization for the enhancement of fracture healing has been recognized to be a therapeutic target, and the subject has been systemically reviewed 13 .…”