Effects of zoledronic acid on osteoblasts in three-dimensional culture

Abstract

International audienceBackground/purpose: Bisphosphonates (BPs) are synthetic drugs with antitumorand bone antiresorptive activities. The use of BPs is suspected to favor the emergence of osteonecrosisof the jaw (ONJ), a putative side effect whose pathogenesis remains unclear. Thus,we aimed to get insights about the impact of BPs on osteoblasts functions, using a threedimensional(3D) culture model, which is suggested to be more similar to the in vivo tissuesthan monolayers.Materials and methods: Effects of low (0.1 mM) and high (10 mM) concentrations of zoledronicacid were investigated on osteoblasts (hFOB 1.19), cultured as multicellular spheroids (MCS).Proliferation, apoptosis, spheroid growth kinetics, and morphology were studied using the 3-(4,5-dimethyl-thiazoyl-2yl) 2,5-diphenyl-tetrazolium bromide (MTT) and acid phosphatase(APH) assays, caspase 3 Western-blotting, phase contrast imaging and scanning electron microscopy(SEM).Results: Proliferation, apoptosis, and spheroid morphology showed that 10 mM zoledronic acid(ZA) induced a significant reduction in the relative viable cell number, correlated with morphologicalalterations of spheroids, and induction of apoptosis. A lower ZA concentration (0.1 mM)promoted cell proliferation without affecting growth kinetics or spheroid morphology.Conclusion: ZA sensitivity of osteoblasts depends on concentration and experimental models.The dual dose-dependent effects of ZA on osteoblasts cultured as spheroids, thereby promotingor inhibiting cell proliferation, may provide opportunities in tissue engineering. At last, thehFOB spheroid culture system represents a valuable model for the exploration of the molecula

Assembly of breast cancer heterotypic spheroids on hyaluronic acid coated surfaces

“…Such experimental set up, i.e. using spherical or quasi‐spherical spheroids, is fundamental for drug screening, as previously reported by different researchers …”

Medication-Related Osteonecrosis of the Jaws Initiated by Zoledronic Acid and Potential Pathophysiology

“…Three publications investigated the role of osteoblasts in bone remodelling and their contribution to MRONJ development. High ZA concentrations were shown to both decrease proliferation levels [24,26,30] and increase apoptosis [26] in osteoblasts. Furthermore, medium conditioned by ZA-treated epithelial cells was able to decrease proliferation and expression of factors (BMP-4, TGF-β2 and ALP) in osteoblasts, suggesting soft tissue involvement in activation of bone remodelling and reduced bone formation ability (A7).…”

“…A total of 11 publications were included in this review (see Figure 2). All of the included studies were in vitro studies: five studies concern oral epithelial cells [20][21][22][23][24], six studies are about oral fibroblasts [20][21][22][25][26][27], three studies are about endothelial cells [23,28,29], three studies are about osteoblasts [24,26,30] and one study is about dental pulp stem cells (DPSC) [25]. The included 11 articles were further quality-assessed according to the aforementioned model.…”

Effect of Bisphosphonates on the Osteogenic Activity of Osteoprogenitor Cells Cultured on Titanium Surfaces

“…Previously, Huang et al and Thibaut et al reported a significant cytotoxic effect on MC3T3-E1 cells and human foetal osteoblasts (hFOBs) with concentrations of ZA higher than 10 μM. 15,16 This may suggest that the negative effect of ZA on cell viability is only significant at concentrations higher than the therapeutic dose. The in vivo study by Pozzi et al supports this notion where it was shown that therapeutic doses of ZA decreased the numbers of osteoblasts per bone perimeter in mice without any statistical significance being reached.…”