Nitrogen-Doped Multiwalled Carbon Nanotubes Enhance Bone Remodeling through Immunomodulatory Functions

Abstract

It has been reported that multiwalled carbon nanotubes (MWCNTs) can reportedly positively affect growth and differentiation of bone-related cells and therefore offer great potential in biomedical applications. To overcome negative immune responses that limit their application, specific doping and functionalization can improve their biocompatibility. Here, we demonstrated that nitrogen-doped carboxylate-functionalized MWCNTs (N-MWCNTs) enhance bone remodeling both in vitro and in vivo with excellent biocompatibility, via stimulation of both bone resorption and formation. We revealed that 0.2 μg/mL N-MWCNTs not only increase the transcription of osteoblastogenic and osteoclastogenic genes but also up-regulate the activities of both TRAP and AKP in the differentiation of bone marrow stromal cells (BMSCs). Additionally, intramuscular administration of N-MWCNTs at a dosage of 1.0 mg/kg body weight enhances bone mineral density and bone mass content in mice, as well as induces potentiated degree of TRAP-and ARS-positive staining in the femur. The positive regulation of N-MWCNTs on bone remodeling is initiated by macrophage phagocytosis, which induces altered production of inflammatory cytokines by immune response pathways, and consequently up-regulates IL1α, IL10, and IL16. These cytokines collectively regulate the central osteoclastogenic transcription factor NFATc1 and osteoblastogenic BMP signaling, the suppression of which confirmed that these factors respectively participate in N-MWCNT-mediated regulation of osteoclastic and osteoblastic bone marrow stem cell activities. These results suggest that N-MWCNTs can be readily generalized for use as biomaterials in bone tissue engineering for metabolic bone disorders.

Analysis of Nanomedicine Efficacy for Osteoarthritis

“…[190] In addition, Li et al obtained nitrogen-containing multilayer carbon nanotubes by modification and found in in vitro studies that nitrogen-containing multilayer carbon nanotubes were able to activate both osteoclast and osteoblast activity, as confirmed by the biomarkers of both, tartrate-resistant acid phosphatase and alkaline phosphatase, and also identified that the osteoclast-associated signaling pathway RANKL was significantly downregulated and the osteoblast-related inducible osteogenic proteins BMP-2 and BMP-4 were activated. [191] In mice in vivo studies, nitrogen-containing multilayer carbon nanotubes also showed positive regulation of osteoblast-associated bone remodeling and osteoclast-associated bone resorption consistent with the in vitro study and the activation of macrophages that also contributed to bone remodeling. [191] These also show the important role played by MSCs in bone as well as cartilage repair.…”

Zuo-Gui-Wan Aqueous Extract Ameliorates Glucocorticoid-Induced Spinal Osteoporosis of Rats by Regulating let-7f and Autophagy

“…In the present study, we demonstrated that DEXA can result in severe bone damage, which was consistent with our previous studies ( 11 , 25 ), indicating a success of the GIOP rat model. Simultaneously, our data showed that DEXA weakened serum AKP activity, which is recognized as an important marker of bone formation ( 26 ). We also verified that DEXA could increase CTSK expression, which is most abundant in osteoclasts ( 27 ), and decrease the expression of Runx2, an important osteoblast transcription factor, which was a benefit for bone formation ( 28 ), in GIOP rats.…”

Nitrogen-Doped Multiwalled Carbon Nanotubes Inhibit Fat Deposition via Immunomodulatory Actions

“…Scientists have shown in mouse models that nitrogen-doped MWCNTs are better tolerated than the pristine MWCNTs, and induce a weaker in ammatory response [11]. Our investigation has demonstrated the enhancement of nitrogen-doped carboxylate-functionalized MWCNTs (N-MWCNTs) on bone growth with good biocompatability [12]. Therefore, N-MWCNTs offer immense opportunities as drug or biomolecule carriers and have great application potential in the treatment of diseases.…”

“…CNTs exhibit amazing functions in immunomodulation, cancer therapy, brain disorder treatment, tissue engineering, and drug delivery [9,10,12,23,24]. With the development of nanotechnology, the evaluation in drug delivery is more than ever.…”

“…Compared with SWCNTs, MWCNTs are composed of multi-layer graphene and have a much wider diameter adjustment range, so they provide a variety of research methods for different biological purposes, such as delivering some large biomolecules and drugs to the cells [6][7][8][9]. Doping and functionalization could e ciently improve their solubility, compatability, and safety [10][11][12]. Scientists have shown in mouse models that nitrogen-doped MWCNTs are better tolerated than the pristine MWCNTs, and induce a weaker in ammatory response [11].…”