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Regulation of osteogenesis and osteoclastogenesis by zoledronic acid loaded on biodegradable magnesium-strontium alloy.

ABSTRACT: Inhibiting osteoclasts and osteoclast precursors to reduce bone resorption is an important strategy to treat osteoclast-related diseases, such as peri-prosthetic osteolysis. In this study, our objective was to study the role of zoledronic acid (ZA), as a highly potent and nitrogen-containing bisphosphonate, in promoting osteogenesis and inhibiting osteoclastogenesis properties of magnesium (Mg)-based implants. ZA was chemically associated with calcium phosphate (CaP) deposited on magnesium-strontium (Mg-Sr) alloy, which was confirmed by the morphological observation, phase composition and drug releasing via SEM, XRD spectrum and High Performance Liquid Chromatography (HPLC), respectively. The in vitro performances indicated that ZA-CaP bilayer coating Mg-Sr alloy could enhance the proliferation and the osteogenic differentiation as well as the mineralization of pre-osteoblasts, however, induce the apoptosis and inhibit the osteoclast differentiation. We further investigated the possible molecular mechanisms by using Quantitative real-time PCR (qRT-PCR) and Western Blotting, and the results showed that ZA-CaP bilayer coating Mg-Sr alloy could regulate the osteogenesis and osteoclastogenesis through the Estrogen Receptor α (ERα) and NF-κB signaling pathway. Moreover, ZA-CaP bilayer coating Mg-Sr alloy could regulate the cross talk of osteoblast-osteoclast and increase the ratio of OPG: RANKL in the co-culture system through OPG/RANKL/RANK signaling pathway, which promoting the balance of bone remodeling process. Therefore, these promising results suggest the potential clinical applications of ZA pretreated Mg-Sr alloys for bone defect repairs and periprosthetical osteolysis due to the excessive differentitation and maturation of osteoclasts.

SUBMITTER: Li M

PROVIDER: S-EPMC6353919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Inflammatory osteolysis induced by wear particles is the major cause of prosthetic loosening after artificial joint replacement, and its prevention and treatment are difficult worldwide. Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response. However, it is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. Zoledronic acid (ZA), an imidazole-containing bisphosphonate, directly affects osteoclasts and prevents bone mineral-related diseases. However, the effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown. Methods: We applied tartrate-resistant acid phosphatase (TRAP) staining to evaluate bone destruction in the interface membranes of patients with aseptic loosening and a control group. A murine calvarial osteolysis model was used to examine the preventative effect of SPHK inhibitors and ZA on osteolysis. Micro-CT scanning, immunohistochemistry (IHC), and histomorphometric analysis were conducted to determine the variations in inflammatory osteolysis. The effects of different drug concentrations on cell viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to confirm the reduced expression of osteoclast-specific genes after drug and titanium treatment. The osteoclast formation and functions of the drugs were analyzed using TRAP staining in vivo and in vitro. The effect of SPHKs/S1P-TRAF2-BECN1 signaling pathways was verified via RT-qPCR and tissue IHC. Results: In this study, we found that SPHK inhibitors (ABC294640 and FTY720) combined with ZA decreased the degree of inflammatory osteolysis in vivo. However, ABC294640 and ZA suppressed osteoclast differentiation and osteoclast-specific genes in vitro. SPHKs regulate the inflammatory osteolysis induced by wear particles by increasing the expression of SPHKs/S1P-TRAF2-BECN1. Conclusion: Our study revealed that wear particles could induce inflammatory osteolysis by upregulating SPHKs/S1P-TRAF2-BECN1 and SPHK inhibitors/ZA inhibit osteoclastogenesis in vitro and prevent inflammatory osteolysis in vivo, suggesting that SPHK inhibitors and ZA can be a new perspective and scientific basis for the prevention and treatment of prosthesis loosening.

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Regulation of osteogenesis and osteoclastogenesis by zoledronic acid loaded on biodegradable magnesium-strontium alloy.

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