The Effects of Cerium Valence States at Cerium Oxide Coatings on the Responses of Bone Mesenchymal Stem Cells and Macrophages

Abstract

Ideal orthopedic coatings should trigger good osteogenic response and limited inflammatory response. The cerium valence states in ceria are associated with their anti-oxidative activity and anti-inflammatory property. In the study, we prepared two kinds of plasma sprayed CeO coatings with different Ce concentrations to investigate the effects of Ce valence states on the response of bone mesenchymal stem cells (BMSCs) and macrophage RAW264.7. Both the coatings (CeO-A and CeO-B) were characterized via XRD, SEM, and X-ray photoelectron spectroscopy. The CeO coatings enhanced osteogenic behaviors of BMSCs in terms of cellular proliferation, alkaline phosphatase (ALP) activity and calcium deposition activity in comparison with the Ti substrate. In particular, the CeO-B coating (higher Ce concentration) elicited greater effects than the CeO-A coating (higher Ce concentration). RT-PCR and western blot results suggested that the CeO-B coating promoted BMSCs osteogenic differentiation through the SMAD-dependent BMP signaling pathway, which activated Runx2 expression and subsequently enhanced the expression of ALP and OCN. With respect to either CeO-A coating or Ti substrate, the CeO-B coating exerted greater effects on the macrophages, increasing the anti-inflammatory cytokines (IL-10 and IL-1ra) expression and suppressing the expression of the pro-inflammatory cytokines (TNF-α and IL-6) and ROS production. Furthermore, it also upregulated the expression of osteoinductive molecules (TGF-β1 and BMP2) in the macrophages. The regulation of cerium valence states at plasma sprayed ceria coatings can be a valuable strategy to improve osteogenic properties and alleviate inflammatory response.

<p>Cerium Oxide Nanoparticles Regulate Osteoclast Differentiation Bidirectionally by Modulating the Cellular Production of Reactive Oxygen Species</p>

“…Some reports indicated that cell viability and osteoblastic differentiation were enhanced by CeO 2 NPs. [18][19][20][21][22]44,45 However, these studies indicated that CeO 2 NPs increase ROS production in acidic intercellular environments and exhibit bidirectional regulatory effects on osteoclast differentiation, which suggests that the application of CeO 2 NPs should take into account the cellular environment and dosedependent effects.…”

“…Previous studies demonstrated that CeO 2 NPs alone or CeO 2 NPs composed of implant coating and scaffolds facilitate cell viability and osteoblastic differentiation of bone mesenchymal stem cells (BMSCs) by scavenging ROS in the cell microenvironment. [18][19][20][21][22][23] In this regard, CeO 2 NPs seem to have some promising effects on bone volume maintenance and bone defect repair. However, the effects of CeO 2 NPs on osteoclastogenesis have not yet been clearly explored.…”

<p>The Advances of Ceria Nanoparticles for Biomedical Applications in Orthopaedics</p>

“…Except for the above experiments, a group result found that a higher Ce 4+ concentration up-regulated the expression of anti-inflammatory cytokines (IL-10 and IL-1RA) and osteoinductive molecules (BMP2 and TGF-1) by macrophages, implying that the regulation of cerium valence might be a valuable strategy for improving osteogenic properties and reducing inflammatory responses. 99 Another application is that the CeO 2 and HA composites attach to other materials with specific mechanical stability, such as AZ91 Mg alloy. 100 Researchers developed manganese (Mn), and strontium (Sr) substituted hydroxyapatite (Mn, Sr-HAP) coatings on the CeO 2 coated AZ91 Mg alloy, which enhanced the corrosion resistance of the whole material to facilitate the clinical application of AZ91 Mg alloy.…”

Cerium- and Iron-Oxide-Based Nanozymes in Tissue Engineering and Regenerative Medicine

“…BMSCs were also used by the Zheng group to assess the osteogenic potential of CO-NPs. However, this time, titanium-based scaffolds were considered [110]. To study the effect of the Ce valence state of the CO-NPs, coatings with high Ce(III) and high Ce(IV) content were prepared-CO-A (67.5% Ce(III)) and CO-B (78.8% Ce(IV)), respectively.…”

“…These data, thus, enhanced the osteogenic potential of CO-NPs with high Ce(IV) content. In a follow-up study, the same group assessed the effect of the Ce valence state on the inflammatory response of RAW264.7 macrophages [110]. In contrast to the bare titanium substrate, coating with CO-NPs resulted in the downregulation of pro-inflammatory cytokines (interleukin (IL)-6 and TNF-α) and the upregulation of anti-inflammatory cytokines (IL-1ra and IL-10).…”