Sodium Fluoride under Dose Range of 2.4–24 μM, a Promising Osteoimmunomodulatory Agent for Vascularized Bone Formation

Fluoride has essential effects on bone physiological activity and is widely used in bone biomaterials modification. However, this beneficial effect is highly related to the dose range and improper dosing can lead to pathological conditions such as fluorosis of bone. Therefore, this study first investigated the dose dependent effect of fluoride on bone regeneration. In the range of 0.24–240 μM, in vivo vascularized bone formation can be achieved via fine-tuning the fluoride concentration, and the peak osteogenic effect was found at 2.4–24 μM. The underlying mechanism is related to the modulation of the osteoimmune environment. Fluoride elicited significant osteoimmunomodulatory effect in modulation of the inflammatory cytokines and expression of osteogenic factors (BMP2, OSM, spermine/spermidine) and angiogenic factor (VEGF, IGF-1) during the early response. Fluorine with the doses of 2.4 and 24 μM could increase polyamines and IGF-1 production in macrophages, thus promoting osteogenesis of BMSCs and angiogenesis of HUVECs. These doses could also inhibit the inflammatory response of macrophages. In vitro osteogenesis and angiogenesis were both improved by the fluorine (2.4 and 24 μM)/macrophage conditioned medium, which is consistent with the in vivo results. These results collectively imply that fluoride is an effective osteoimmunomodulatory agent that can regulate both osteogenesis and angiogenesis. “Osteoimmune-smart” bone biomaterials can be developed via incorporating fluorine, and the release concentration should be controlled within the range of 2.4–24 μM for improved bone formation.