The effects of mandibular osteotomy on maxillary orthodontic tooth movement and bone remodelling in a rat model.

OBJECTIVES: The accelerated tooth movement phenomenon after orthognathic surgery has been observed. However, the underlying mechanism remains unclear. There is no experimental study showing the effect of orthognathic surgery on orthodontic tooth movement of the opposing jaw. Therefore, the present study aimed at investigating if mandibular osteotomy enhances maxillary tooth movement and bone remodelling. MATERIALS AND METHODS: Fifty-four male Sprague-Dawley rats were randomly divided into two groups: maxillary tooth movement (TM) and maxillary tooth movement + mandibular surgery (TM + MS). The orthodontic force was delivered to move the left maxillary first molar mesially. The surgical intervention was performed on the left mandible. Microcomputed tomography, histological analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction were used to assess changes at 3, 7, and 21 days after surgery. RESULTS: The mandibular osteotomy accelerates the rate of maxillary tooth movement with decreased bone volume fraction on the seventh day. Bone resorption was observed on the third and seventh day after mandibular osteotomy. It was found that serum interleukin-1ß level increased significantly in the TM + MS group compared with the TM group, as well as the high expression level of cathepsin K and tumour necrosis factor receptor-associated factor 5 of the orthodontic tooth on the third and seventh day after mandibular osteotomy. CONCLUSION: Data from the present study suggested that mandibular osteotomy accelerates maxillary osteoclast activity and post-operative tooth movement, providing evidence for accelerated tooth movement phenomenon after orthognathic surgery.

Mandibular osteotomy-induced hypoxia enhances osteoclast activation and acid secretion by increasing glycolysis.

The rapid bone remodeling after osteotomy has been reported for a long time. However, the underlying mechanism promoting the active bone reconstruction was still to be elucidated. Since not only the bone, blood vessels, and supportive tissues, but also the local microenvironment were destroyed, if the changes on the cell metabolism was contributed to the accelerated bone remodeling came into sight. In present study, we found that the mandibular osteotomy in rabbit activated osteoclasts, as well as the expression of hypoxia-inducible factor 1α (HIF-1α) in alveolar bone. Hypoxia or HIF-1α could enhanced osteoclastogenesis, bone absorption, and lactic acid concentration in receptor activator of nuclear factor κΒ ligand-induced RAW264.7 cells. Coincided with the upregulated HIF-1α expression, HIF-driven glycolytic enzymes, such as lactate dehydrogenase A (LDHA), glucokinase (GCK), pyruvate kinase M2 (PKM2), and phosphofructokinase1 (PFK1), were found massively increased in both hypoxic RAW264.7 cells and the alveolar HIF-1α-positive osteoclasts after mandibular osteotomy. Knockdown of HIF-1α suppressed not only the hypoxia-mediated glycolysis, but also the hypoxia-induced acid secretion and bone resorption in RAW264.7 cells. Application of inhibitor on glycolysis gave rise to the similar results as HIF-1α knockdown. Our findings suggested that hypoxia-driven glycolysis in osteoclasts was an adaptive mechanism to permit alveolar bone remodeling after mandibular osteotomy.

Activity and morphologic changes in the mandible after mandibular osteotomy.

INTRODUCTION: Orthognathic surgery accelerates orthodontic tooth movement, and tooth movement accelerates with demineralized bone and accelerated bone remodeling. The purpose of this study was to ascertain whether orthognathic surgery induces accelerated bone remodeling. The research design included a human model and an animal model. METHODS: The levels of serum tartrate resistant acid phosphatase-5b (TRAP) and bone alkaline phosphatase (BALP) were measured in 15 patients after sagittal split ramus osteotomy. For the animal study, 18 rabbits were divided into 6 groups: a control group and 5 surgery groups. The rabbits in the surgery groups had osteotomies in the molar regions of the mandible. Changes in bone mass of the anterior mandibles were examined by microcomputed tomography, and changes in osteoblast and osteoclast numbers were analyzed by real-time polymerase chain reaction, hematoxylin and eosin staining, TRAP staining, and alkaline phosphatase staining. RESULTS: In the 15 patients, TRAP-5b increased from 1 to 8 weeks postoperatively, and BALP increased significantly in 2 weeks postoperatively. In the rabbits, the levels of mRNA expression of TRAP were increased at 3 weeks, and matrix metalloproteinase 9 was increased at 4 and 8 weeks, whereas mRNA expression of BALP and bone morphogenetic protein 2 were increased at 4 weeks. Bone loss was detected from 1 week postoperatively and reached the maximum at 3 weeks; and bone mass and mechanical structure did not recoverer to preoperative levels until 8 weeks postoperatively. CONCLUSIONS: These findings show active bone remodeling induced by osteotomy.

IL-6 Enhances Osteocyte-Mediated Osteoclastogenesis by Promoting JAK2 and RANKL Activity In Vitro.

BACKGROUND/AIMS: Evidence suggests that IL-6 affects bone mass by modulating osteocyte communication towards osteoclasts. However, the mechanism by which IL-6 enhances osteocyte-mediated osteoclastogenesis is unclear. We aimed to investigate the inflammatory factors in serum after orthodontic surgery and their relationship between osteocytes and osteoclasts. METHODS: Serum was obtained from 10 orthognathic surgery patients, and inflammatory factors were detected by ELISA. We treated the osteocyte-like cell line MLO-Y4 with recombinant mouse IL-6 and IL-6 receptor (IL-6R), and used quantitative RT-PCR and Western blotting to explore Receptor activator of nuclear factor-κB ligand (RANKL) expression at both the mRNA and protein level. MLO-Y4 cells were co-cultured with osteoclast precursor cells, and the formation of osteoclasts was detected by tartrate-resistant acid phosphatase (TRAP) staining. To explore the role of JAK2 in the osteocyte-mediated osteoclastogenesis, AG490, a JAK2 inhibitor, was used to inhibit the JAK2-STAT3 pathway in osteocytes. RESULTS: In our study, we found that IL-6 and RANKL were stimulated in serum 3-7 days after orthognathic surgery. Therefore, IL-6 and IL-6 receptor enhanced the expression of RANKL at both the mRNA and protein level in MLO-Y4. Furthermore, when MLO-Y4 cells were co-cultured with osteoclast precursor cells, it significantly stimulated osteoclastogenesis. Our study indicated that osteocytes could promote osteoclastic differentiation and the formation of TRAP-positive multinucleated cells after stimulation with IL-6 and IL-6R. Our results also indicated that treatment with IL-6 and IL-6R increased RANKL mRNA expression and the RANKL/OPG expression ratio. Meanwhile, the phosphorylation of Janus kinase 2 (JAK2) and Signal transducer and activator of transcription (STAT3) also correlated with RANKL levels. Furthermore, we investigated the effects of a specific JAK2 inhibitor, AG490, on the expression of RANKL in osteocyte-like MLO-Y4 cells and osteocyte-mediated osteoclastogenesis. The results showed that AG490 inhibited (p)-JAK2 and RANKL expression. Osteoclastic differentiation was decreased after pretreatment in MLO-Y4 with mouse IL-6/IL-6R and AG490; therefore, we concluded that IL-6 increased osteocyte-mediated osteoclastic differentiation by activating JAK2 and RANKL. CONCLUSION: The effects of IL-6/il-6R and AG490 on osteocyte-mediated osteoclastogenesis contribute to our understanding of the role of inflammatory factors in the interaction between osteocytes and osteoclast precursors. IL-6 and RANKL are key factors for bone remodelling after the orthodontic surgery, and their roles in bone remodelling may be fundamental mechanisms accelerating tooth movement by orthodontic surgery.

Viral Mimicking Polyplexes as Hierarchical Unpacking Vectors for Rheumatoid Arthritis Treatment.

Nano-delivery systems hold great promise for the treatment of rheumatoid arthritis (RA). Current research efforts are primarily focused on enhancing their targeting capabilities and efficacy. Here, this study proposes a novel viral-mimicking ternary polyplexes system for the controlled delivery of the anti-inflammatory drug Cyclosporin A (CsA) to effectively treat RA. The ternary polyplexes consist of a nanogel core loaded with CsA and a hyaluronic acid shell, which facilitates CD44-mediated targeting. By mimicking the Trojan Horse strategy employed by viruses, these polyplexes undergo a stepwise process of deshielding and disintegration within the inflamed joints. This process leads to the release of CsA within the cells and the scavenging of pathogenic factors. This study demonstrates that these viral-mimicking ternary polyplexes exhibit rapid targeting, high accumulation, and prolonged persistence in the joints of RA mice. As a result, they effectively reduce inflammation and alleviate symptoms. These results highlight the potential of viral-mimicking ternary polyplexes as a promising therapeutic approach for the targeted and programmed delivery of drugs to treat not only RA but also other autoimmune diseases.

Abalone-Inspired Adhesive and Photo-Responsive Microparticle Delivery Systems for Periodontal Drug Therapy.

Antibiotics provide promising strategies for treating periodontitis, while their delivery and controllable release with desired oral retention remain challenging. Here, inspired by the unique suction-cup structures of abalones, a novel adhesive and photo-responsive microparticle (MP) delivery system is developed to treat periodontitis through microfluidic electrospray technology. Such MPs are generated by quickly ionic cross-linking of sodium alginate together with photo-curing of poly(ethylene glycol) diacrylate of the distorted microfluidic droplets during their high-speed dropping into calcium chloride solution. Attributing to their unique concave structures, the abalone-inspired MPs exhibit desired underwater adhesion ability and stability under running water. In addition, due to the loading of antibiotics minocycline hydrochloride and near-infrared (NIR)-responsive black phosphorus during their fabrication, the resultant MPs can not only eradicate bacteria directly, but also realize a controllable and effective drug release upon NIR irradiation. Based on these features, it is demonstrated from in vivo periodontitis that the abalone-inspired MPs are firmly adhesive and can controlled-release drugs on the tooth, and thus have outstanding antibacterial efficacy against Porphyromonas gingivalis. These results indicate the particular values of the abalone-inspired MPs for oral-related disease treatment.