Iron Oxide Nanoparticles on Bone Remodeling: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Jiancheng Yang.

Iron oxide nanoparticles (IONPs) are extensively used in bone-related studies as biomaterials due to their unique magnetic properties and good biocompatibility. Through endocytosis, IONPs enter the cell where they promote osteogenic differentiation and inhibit osteoclastogenesis in vivo. This result is further supported by in-vivo findings, showing that osteoblasts and osteoclasts internalize the IONPs, yielding superior bone regeneration and weaker bone resorption. Therefore, IONPs  have a potential clinical application value to promote bone regeneration and prevent osteoporosis.

  • iron oxide nanoparticles
  • bone remodeling
  • osteoblast
  • osteoclast

1. Introduction

Due to in-depth research on magnetic nanomaterials in the biomedical field, medical magnetic nanomaterials now have special designs and standards. For clinical applications, safety is the most important factor, so not all magnetic nanomaterials have the potential to be clinically used in the future. Fe3O4 and γ-Fe2O3 solid-phase materials are easy to synthesize and have good chemical stability, magnetic properties, and biocompatibility[1]. Iron oxide nanoparticles (IONPs) have good biosafety and are the most promising magnetic nanomaterials in clinical practice[2]. Importantly, IONPs are the only inorganic functional nanomaterials that have been approved by the Food and Drug Administration (FDA) for clinical application. Over the years, many different IONPs have been evaluated in a wide variety of biomedical applications, including magnetic resonance imaging, tissue engineering, magnetic field drug targeting, and gene therapy[2]. IONPs also change some biological functions of cells. For example, studies have found that IONPs promote the polarization of tumor-associated macrophages into a pro-inflammatory type, thereby inhibiting tumor growth[3]. As a result, the medicinal value of IONPs should be developed based on the relevant biological effects rather than being used only as a nanomaterial.
Currently, the U.S. FDA has approved an IONP, named ferumoxytol (Feraheme), for the treatment of anemia in patients with chronic kidney disease; this is currently the only IONP used for clinical treatment[4]. Bone is a metabolically active tissue that is continuously being remodeled. Two major cell types involved in bone remodeling are osteoblasts, which are responsible for new bone tissue formation, and osteoclasts, which are responsible for bone resorption[5]. Over the past decade, a large number of in vitro studies demonstrated that IONPs promote osteoblast differentiation and inhibit osteoclast formation, whereas in vivo studies showed that IONPs accelerate bone defect repair and prevent bone loss[1]. Consequently, IONPs have certain application potential in bone tissue engineering and osteoporosis treatment.

2. Effects of Iron Oxide Nanoparticles on Bone Remodeling

2.1. Effects of Iron Oxide Nanoparticles on Osteoblasts

As early as 2008, Pareta et al.[6] used IONPs to study osteoblast proliferation and confirmed that calcium-phosphate-coated γ-Fe2O3 nanoparticles significantly increased the density of osteoblasts (i.e., promoted cell proliferation). Subsequently, Tran et al.[7] showed that hydroxyapatite (HA)-coated Fe3O4 nanoparticles significantly promoted the production of alkaline phosphatase (ALP), collagen, and calcium in osteoblasts, indicating that IONPs promote osteogenic differentiation; the authors further investigated the mechanism by which IONPs promote osteoblast differentiation and found that IONPs adsorbed a large amount of fibronectin, which can increase the function of osteoblasts, and upregulated the expression of genes related to osteoblast differentiation[8]. In addition, the authors found that osteoblasts uptake HA-coated IONPs into the cytoplasm via receptor-mediated endocytosis and increase intracellular calcium levels, which may be another reason why HA-coated IONPs promote osteoblast functions[9]. However, other IONPs coated with noncalcium materials can also promote osteoblast activity. For example, Shi et al.[10] found that chitosan-coated IONPs promoted osteoblast proliferation, reduced cell membrane damage, increased ALP activity, and enhanced extracellular calcium deposition. Yin et al.[11] treated MG-63 cells, an osteoblast cell line, with Fe3O4 nanoparticles and found that cell proliferation and ALP activity were significantly promoted. Stem cells have the ability to differentiate into a variety of cells, including osteoblasts. Xiao et al.[12] found that IONPs promoted cell proliferation, reduced apoptosis, increased ALP activity and mineralization nodule formation, and upregulated the expression of genes related to osteogenic differentiation in rat adipose-derived stem cells (ADSCs). Xia et al.[13] generated a scaffold by incorporating γFe2O3 and αFe2O3 nanoparticles into calcium phosphate cement (CPC). The authors found that human dental pulp stem cells (hDPSCs) seeded in this scaffold experienced increased osteogenic differentiation, ALP secretion, and mineral matrix synthesis compared with those seeded in scaffolds without IONPs, demonstrating that the osteogenic differentiation of hDPSCs was significantly promoted via the incorporation of IONPs into CPC. Similarly, Fe3O4-incorporated IONP–CPC scaffolds also enhanced the osteogenic differentiation of hDPSCs and promoted mandibular bone defect repair in rats[14]. In addition, studies have shown that IONPs have peroxidase activities[15]. Hydrogen peroxide (H2O2) was found to play an important role in the process of cell proliferation[16]. Huang et al.[17] treated human bone-derived mesenchymal stem cells (hBMSCs) with ferucarbotran (Resovist), an IONP approved for clinical liver MRI contrast agents, and found that ferucarbotran promoted cell proliferation by reducing intracellular H2O2 levels. These results indicate that IONPs have the ability to promote the proliferation and osteogenic differentiation of osteoblasts and stem cells in vitro. Mechanistically, numerous studies have revealed that IONPs enhance osteogenic differentiation through multiple signaling pathways. Wnt signaling is a crucial pathway that mediates osteogenesis. In the classical Wnt pathway, β-catenin acts as a key transcriptional coactivator, transmitting extracellular signals to the nucleus to activate downstream target genes such as RUNX2[18]. Xia et al.[19] revealed that γ-Fe2O3-loaded CPC scaffolds promoted the osteogenic differentiation of hDPSCs and significantly upregulated the gene expression of WNT1, RUNX2, ALP, COL1, and OCN. Moreover, β-catenin protein expression was increased, indicating that γ-Fe2O3-loaded CPC scaffolds activate Wnt/β-catenin signaling and downstream target genes. In osteoblast differentiation, increased osteoblastogenesis is dependent on the activation of β-catenin through the inhibition of GSK-3β[20], and the PI3K/Akt pathway can inhibit GSK-3β and activate β-catenin[21]. Yu et al.[22] developed a polysaccharide-based iron oxide nanoparticle (Fe2O3@PSC) and found that it has the ability to enhance osteoblast differentiation in MC3T3-E1 cells. A Western blotting assay showed that phosphorylated Akt, phosphorylated GSK-3β, and β-catenin were markedly upregulated. The authors proposed that Fe2O3@PSC promoted osteogenic differentiation by activating the Akt-GSK-3β-β-catenin signaling pathway. Mitogen-activated protein kinase (MAPK) includes three classic pathways, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), which play a key role in skeletal development and bone homeostasis, particularly in osteoblast commitment and differentiation[23][24]. Wang et al.[25] found that polyglucose-sorbitol-carboxymethyether (PSC) coated IONPs enhanced the expression of phosphorylated MEK1/2 and ERK1/2, indicating that IONPs activate the classic ERK-MAPK signaling pathway in hBMSCs. As a result, downstream genes of this pathway such as bone morphogenic protein (BMP2) and RUNX2 were upregulated to promote osteogenic differentiation. BMP2 is a signal molecule of the transforming growth factor-beta (TGF-β) superfamily and plays a crucial role in bone formation by activating the canonical Smad-dependent pathway or noncanonical-MAPK signaling pathway[26]. Lu et al.[27] fabricated a magnetic SrFe12O19 nanoparticle-modified mesoporous bioglass (BG) and chitosan (CS) porous scaffold (MBCS) to treat hBMSCs and found that this scaffold upregulated BMP2 and phosphorylated Smad1/5 expression and promoted the expression of osteogenic-related genes including RUNX2, OCN, COL1, and ALP, suggesting that magnetic MBCS scaffolds enhance osteogenic gene expression by activating the BMP-2/Smad signaling pathway. These in vitro studies indicate that IONPs or IONP-loaded scaffolds accelerate osteogenic differentiation through the Wnt/β-catenin, Akt-GSK-3β-β-catenin, MAPK, and BMP-2/Smad signaling pathways (Figure 1a).
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Figure 1. (a) Schematic illustration of IONP-promoted osteogenic differentiation in osteoblasts and stem cells. Classical Wnt/β-catenin, Akt-GSK-3β-β-catenin, MAPK, and BMP-2/Smad signaling pathways are activated by IONPs. Thus, osteoblastogenesis-related gene transcription downstream is markedly promoted, leading to enhancement of osteogenic differentiation. (b) Schematic illustration of IONP-attenuated osteoclastogenesis in BMMs. IONPs upregulated p62 expression by increasing the binding of CYLD to the TRAF6–p62–CYLD complex, resulting in repressive ubiquitination of TRAF6 and inhibition of RANKL-induced signaling pathway such as NF-κB and MAPK signals. As a result, transcription of osteoclastogenesis-related genes was obviously blocked, leading to blockage of osteoclastogenesis.
In line with the in vitro studies, some in vivo studies have shown that scaffolds complexed with IONPs can promote bone formation. Hu et al.[28] implanted superparamagnetic IONP-loaded gelatinous sponges in rat incisor sockets, while gelatinous sponges without IONPs served as controls. Based on micro-CT and histological observations, the authors found greater formation of new bone compared with the blank control group at 4 weeks, suggesting that these IONPs induce active osteogenesis in vivo. Liao et al.[29] showed that PSC-coated IONPs promoted the differentiation of human precartilaginous stem cells (hPCSCs) into osteoblasts in vitro. In vivo, the authors incorporated IONP-labeled PCSCs in a novel methacrylated alginate and 4-arm poly(ethylene glycol)-acrylate (4A-PEGAcr) based interpenetrating polymeric printable network (IPN) hydrogel and implanted them into femoral defects in rats. The results of the micro-CT and histological analysis revealed that the implantation of IONP-labeled PCSCs significantly enhanced bone formation. Singh et al.[30] designed magnetic nanofibrous scaffolds by incorporating magnetic nanoparticles (MNPs) into poly(caprolactone) (PCL). The PCL–MNP nanofibrous scaffolds were subcutaneously implanted at the site of radial segmental defects. Histological images showed the favorable tissue compatibility and bone regenerative ability of the PCL–MNP nanofibers. Panseri et al.[31] obtained magnetic hydroxyapatite–collagen scaffolds via the nucleation of biomimetic hydroxyapatite and superparamagnetic IONPs on self-assembling collagen fibers. These magnetic scaffolds were implanted in rabbit tibial mid-diaphysis and distal femoral epiphysis. Histopathological screening showed that no inflammatory reaction occurred and that the bone-healing rate was significantly enhanced. Shuai et al.[32] constructed magnetic poly-l-lactide–polyglycolic acid (PLLA–PGA) scaffolds by incorporating Fe3O4 nanoparticles. The magnetic scaffolds were implanted into rabbit radius bone defects, and the results indicated that these scaffolds markedly induced substantial blood vessel tissue and new bone tissue formation at 2 months post-implantation, indicating that PLLA–PGA magnetic scaffolds offered excellent bone regeneration capabilities. Implantation of SrFe12O19–MBCS scaffolds into rat calvarial defects showed a significant increase in BMD and new bone areas at 12 weeks, suggesting that magnetic MBCS scaffolds enhance new bone regeneration in vivo[27]. Zhao et al.[33] incorporated nano-hydroxyapatite (nHAP) and Fe3O4 nanoparticles into the chitosan–collagen (CS–Col) organic matrix to obtain a magnetic CS–Col–Fe3O4–nHAP scaffold. A skull defect model of rats demonstrated that the CS–Col–Fe3O4–nHAP scaffold had better tissue compatibility and higher bone regeneration abilities when implanted into the skull defects compared with the control group. Overall, these magnetic scaffolds formed by incorporating IONPs seem to be promising for bone defect repair in the regenerative medicine field. The above findings all indicate that IONPs promote osteoblast differentiation in vitro and accelerate bone formation and bone defect repair in vivo. However, not all IONPs are able to promote osteogenic differentiation. For example, citric-acid-coated IONPs reduced the cell viability of ADSCs and BMSCs and inhibited their adipogenic and osteogenic differentiation abilities[34][35], which may be related to the fact that citric acid can inhibit the proliferation of osteoblasts[36].

2.2. Effects of Iron Oxide Nanoparticles on Osteoclasts

Osteoclasts are differentiated from bone marrow macrophages (BMMs) under the induction of the receptor activator for nuclear factor-κ B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) and are the main cells that perform bone resorption. Compared with osteoblasts, there are fewer studies on IONPs on osteoclasts. Li et al.[37] treated mouse BMMs with PSC-coated IONPs and HA-coated IONPs, finding that both IONPs significantly inhibited osteoclast formation and downregulated osteoclast-differentiation-related gene expression. Postmenopausal osteoporosis is a disease characterized by reduced BMD, damaged bone microstructure, and increased bone fragility induced by increased osteoclast activity[38]. Bilateral ovariectomy (OVX) in animals is the most commonly used model used to mimic postmenopausal osteoporosis. Liu et al.[39] found that ferucarbotran and Feraheme inhibited the differentiation of mouse BMMs into osteoclasts, whereas the intravenous injection of two types of IONPs markedly inhibited bone resorption and OVX-induced bone loss in OVX mice. Zheng et al.[40] also revealed that PSC-coated IONPs inhibited osteoclast differentiation and prevented bone loss caused by OVX. In addition, the authors prepared IONPs loaded with alendronate, a drug used for the treatment of osteoporosis, and found that IONPs could target the bone tissue; the IONPs’ ability to inhibit bone loss was significantly better than that of alendronate alone. Iron is an essential element involved in multiple life activities of the human body, including bone metabolism[41]. However, excessive iron can induce osteoporosis by activating osteoclast activity[42]. Yu et al.[22] showed that the PSC-loaded Fe2O3 nanoparticles inhibited osteoclast differentiation of Raw 264.7 cells in vitro and prevented iron-accumulation-related osteoporosis in vivo. During osteoclast differentiation, RANKL binds to its receptor RANK on BMMs and activates many signaling pathways, including MAPKs (ERK, JNK, and p38) and nuclear factor-kB (NF-kB), by recruiting the signaling-adaptor molecule TNF receptor-associated factor 6 (TRAF6)[43]. Among them, the ubiquitination of TRAF6, which involves the important adaptor protein p62 and deubiquitinase cylindromatosis (CYLD), is a key process[44]. Liu et al.[39] revealed that IONPs enhanced the expression of p62, which resulted in the recruitment of CYLD and promoted the deubiquitination of TRAF6. Moreover, the downstream MAPK and NF-κB signaling pathway was inhibited, leading to decreased expression of osteoclastogenesis-related genes, including NFATC1, ACP5, CALCR, CTSK, and c-SRC. Similarly, Yu et al.[22] demonstrated that Fe2O3@PSC nanoparticles suppressed osteoclast differentiation by inhibiting the MAPK and NF-κB pathways in vitro. Therefore, IONPs can inhibit osteoclast differentiation through the retardation of MAPK and NF-κB signaling pathways (Figure 1b).

3. Outlook

Although the effect of IONPs on bone remodeling has been well studied, there remain some interesting unresolved questions regarding the effects of IONPs on bone remodeling that deserve exploration in the future. Osteocytes descend from osteoblasts encapsulated by a mineralized bone matrix and constitute over 90% of bone cells in the adult skeleton[45]. These cells act as a coordinator in bone remodeling, modulating the differentiation and function of osteoclasts and osteoblasts through distinct signaling pathways, including the RANKL/OPG axis and SOST/Dkk1/Wnt axis[46]. Although osteocytes are very important for bone remodeling, there is no report on the effects of IONPs on osteocytes. This subject would be a rewarding direction for future studies, as osteocytes play a crucial role in bone homeostasis.

Previous studies on IONPs related to bone repair or osteoporosis have mainly focused on the biological effects of IONPs in animal or cell experiments. Thus, rigorous clinical trials in humans are needed before translating these findings into clinical practice. Moreover, toxicity is the most important evaluation index in clinical therapy. However, existing studies fail to evaluate the safety of IONPs in vivo. The toxicity of IONPs should be considered in a dose-, treatment-, and time-dependent manner[47]. Therefore, the absorption, distribution, metabolism, and toxicity of IONPs after implanting a composite scaffold containing IONPs in vivo should be explored in future studies.

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