Strontium ranelate interferes with the release and function of matrix vesicles

The bone tissue plays a crucial role in the organism's systemic regulation. Many conditions are commonly associated with the loss of bone mass and fractures. Using bioactive nanoparticles (NPs) that mimic the structure of bone apatite is a compelling approach to bone healing. Strontium ions (Sr2+) can control osteoblast activity and affect extracellular matrix (ECM) mineralization. We hypothesized here that Sr2+ affects mineralization in two ways: (1) at a molecular level by regulating indirectly osteogenic genes, and (2) by physically modulating proteins presented in the matrix vesicles (MV) membrane. Here we observed that Sr2+ upmodulated the activation of Erk1/2 and CREB signaling pathways. This upregulation was not observed on the gene expression level, since Sr2+ did not interfere with the expression of osteogenic-related genes (Runx2, Sp7, Ocn, Smpd3, and Alp). The effect of strontium on the release of MV was studied by NTA and lipidomic analysis was also applied to characterize the MVs´ lipid profile. Results demonstrate that Sr2+ decreased the release of matrix vesicles, albeit low doses of Sr2+ (0.1mM) increase the efficiency of MV to start mineralization. Finally, the lipidomic analysis demonstrated a change in lipid pattern when the cells-derived MVs were exposed to different concentrations of strontium. Biomineralization key lipids (e.g., Cer and SM) were upregulated in MVs released from cells treated with low and high doses of Sr2+. In conclusion, this work demonstrated that Sr2+ affects the release and function of matrix vesicles in a dose-dependent manner. Such an effect is likely related to both the modulation of osteogenic-related pathways and the modulation of the lipid profile found in the MV membrane.