Dancr-BRG1 regulates Nfatc1 transcription and Pgc1ß-dependent metabolic shifts in osteoclastogenesis.

Long non-coding RNA (lncRNA) serves as a vital regulator of bone metabolism, but its role in pathologically overactive osteoclast differentiation remains elusive. Here, we identify lncRNA Dancr (Differentiation Antagonizing Non-protein Coding RNA) as a critical suppressor of osteoclastogenesis and bone resorption, which is down-regulated in response to estrogen deficiency. Global or osteoclast-specific Dancr Knockout mice display significant trabecular bone deterioration and enhanced osteoclast activity, but minimal alteration of bone formation. Moreover, the bone-targeted delivery of Dancr by Adeno-associated viral remarkably attenuates ovariectomy-induced osteopenia in mice. Mechanistically, Dancr establishes a direct interaction with Brahma-related gene 1 to prevent its binding and preserve H3K27me3 enrichment at the nuclear factor of activated T cells 1 and proliferator-activated receptor gamma coactivator 1-beta promoters, thereby maintaining appropriate expression of osteoclastic genes and metabolic programs during osteoclastogenesis. These results demonstrate that Dancr is a key molecule maintaining proper osteoclast differentiation and bone homeostasis under physiological conditions, and Dancr overexpression constitutes a potential strategy for treating osteoporosis.

Artificial intelligence-based radiomics in bone tumors: Technical advances and clinical application.

Radiomics is the extraction of predefined mathematic features from medical images for predicting variables of clinical interest. Recent research has demonstrated that radiomics can be processed by artificial intelligence algorithms to reveal complex patterns and trends for diagnosis, and prediction of prognosis and response to treatment modalities in various types of cancer. Artificial intelligence tools can utilize radiological images to solve next-generation issues in clinical decision making. Bone tumors can be classified as primary and secondary (metastatic) tumors. Osteosarcoma, Ewing sarcoma, and chondrosarcoma are the dominating primary tumors of bone. The development of bone tumor model systems and relevant research, and the assessment of novel treatment methods are ongoing to improve clinical outcomes, notably for patients with metastases. Artificial intelligence and radiomics have been utilized in almost full spectrum of clinical care of bone tumors. Radiomics models have achieved excellent performance in the diagnosis and grading of bone tumors. Furthermore, the models enable to predict overall survival, metastases, and recurrence. Radiomics features have exhibited promise in assisting therapeutic planning and evaluation, especially neoadjuvant chemotherapy. This review provides an overview of the evolution and opportunities for artificial intelligence in imaging, with a focus on hand-crafted features and deep learning-based radiomics approaches. We summarize the current application of artificial intelligence-based radiomics both in primary and metastatic bone tumors, and discuss the limitations and future opportunities of artificial intelligence-based radiomics in this field. In the era of personalized medicine, our in-depth understanding of emerging artificial intelligence-based radiomics approaches will bring innovative solutions to bone tumors and achieve clinical application.

Hemi-atlas resection by combined approach: case report, literature review, and technical note.

PURPOSE: Hemivertebra within the craniovertebral junction is a rare but complex spinal deformity. Torticollis caused by hemi-atlas is extremely rare. There is no consensus on the treatment of these patients. We present our experience with one case of hemi-atlas excision and torticollis correction via a combined anterior-posterior surgical approach and short-segment fixation. METHODS: An 11-year-old girl with progressive torticollis due to hemi-atlas underwent surgery consisting of combined anterior-posterior hemivertebra resection and instrumentation and had a follow up of 20 months. Pre- and postoperative radiographic features, as well as clinical outcomes, were evaluated. RESULTS: The patient had complete recovery of torticollis at a 20-month follow-up. Radiographs showed favorable deformity correction, well-balanced coronal and sagittal alignment, and solid bony fusion. CONCLUSION: For patients with congenital cervical hemivertebra within the craniovertebral junction, combined anterior-posterior hemivertebra resection with instrumentation allows for satisfactory deformity correction and good cosmetic improvement.

Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait. OBJECTIVE: We aimed to explore the oligogenic nature of this disease and identify novel AIS genes. METHODS: We analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients. RESULTS: Multiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB. In functional studies, we found that the AIS-associated FLNB variants altered the protein's conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis. CONCLUSION: Our data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.

Comparison between tension band and cerclage with X-Plate and lag screws in treatment of comminuted patellar fractures.

BACKGROUND: Comminuted patellar fractures are not rare, and the ideal treatment method remains controversial. The present study was conducted to evaluate effects and compare complications of two different methods used to treat comminuted patellar fractures. METHODS: From March 2010 to August 2016, 102 cases of 34-C2 or 34-C3 comminuted patellar fractures were treated at our hospital, wherein patients received two different treatments: titanium cable tension band with cerclage method (group A) and intrafragmentary screws with X-shaped plating technique (group B). At follow-ups, articular step-off, range of motion (ROM), Lysholm scores, time of union, and complications were recorded and analyzed. Radiographic and clinical data as well as rate of complications were statistically analyzed. RESULTS: In total, 87 patients were included in the final analysis (n = 47 in group A and n = 40 in group B). No significant differences were noted in terms of cost of implant, age, gender, rate of 34-C3 fractures, rate of layered inferior pole fractures, postoperative articular step-off and union time. At 2-year follow-up, average Lysholm scores, ROM and rate of complications were (89.0 ± 4.5), (122°±12°) and (27.7%) in group A and (90.2 ± 3.9), (124°±11°) and (17.5%) in group B, respectively, with no significant differences (p > 0.05). The mean time of surgery in group B was shorter than that in group A with significant difference (p < 0.05). CONCLUSIONS: Treatment using the intrafragmentary screws and plate method for amenable comminuted patellar fractures achieved similar complication rate and favorable functional outcomes at the 2-year follow-up, which was comparable to the titanium cable tension band with cerclage method. Thus, the intrafragmentary screws and plate method is effective, safe and convenient for 34-C2/C3 comminuted patellar fractures, especially appropriate for patients with layered fragments.

Modified C7 pedicle subtraction osteotomy for the correction of cervicothoracic kyphosis.

BACKGROUND: Osteotomies in the cervical spine are technically challenging. The purpose of this study was to evaluate the feasibility of the modified pedicle subtraction osteotomy (PSO) technique at C7 to be used for the treatment of cervicothoracic kyphosis secondary to ankylosing spondylitis. METHODS: A total of 120 cervical spine computed tomography (CT) scans (of 82 male and 38 female patients) were evaluated. The scans were taken parallel to the middle sagittal plane and the sagittal plane intersecting the pedicles. Simulated osteotomy was performed by setting the apex of the wedge osteotomy at different points, and morphologic measurements were obtained. Seven patients with cervicothoracic kyphosis who underwent a modified PSO at C7 between May 2009 and June 2015 were retrospectively evaluated. The mean follow up was 32.9 months (range 21-54 months). Preoperative and postoperative chin-brow vertical angle (CBVA), sagittal vertical axis (SVA) and sagittal Cobb angle of the cervical region were reviewed. The outcomes were analyzed through various measures, which included the 36-Item Short Form Health Survey (SF-36) and a visual analog scale for neck pain. RESULTS: In this morphometric study, a modified PSO was performed on 87 patients (59 male and 28 female) with a reasonable ratio of 72.5%. In the case series, radiographic parameters and health-related quality-of-life measures were found to show significant postoperative improvement in all patients. No major complications occurred, and no implant failures were noted until the latest follow up. CONCLUSIONS: The modified PSO is a safe and valid alternative to the classic PSO, allowing for excellent correction of cervical kyphosis and improvement in health-related quality-of-life measures.

Functional variants of hepatocyte growth factor identified in patients with adolescent idiopathic scoliosis.

The genetic etiology of adolescent idiopathic scoliosis (AIS) remains obscure. Whole-genome sequencing was performed in four members of one family. Then, we performed a rigorous computational analysis to determine the deleterious effects of the identified variants. Furthermore, the structural differences between the native hepatocyte growth factor (HGF) protein and a protein encoded by an HGF variant containing one mutation (p.T596M) were analyzed using molecular dynamic stimulation. A novel heterozygous mutation (p.T596M) within the HGF gene was identified and found to cosegregate with scoliosis phenotypes in three affected family members. Subsequent modeling and structure-based analyses supported the theory that this mutation is functionally deleterious. Functional analyses demonstrated that the HGF p.T596 M mutation changed the ability of the HGF protein to be secreted and impaired migration and invasion in HEK293T cells. Furthermore, an HGF knockdown zebrafish model exhibited a curly tailed phenotype. Mutation in HGF is associated with an autosomal dominant pattern of inheritance of AIS. This finding increases our understanding of the genetic heterogeneity of AIS.

Asymmetric expression of GPR126 in the convex/concave side of the spine is associated with spinal skeletal malformation in adolescent idiopathic scoliosis population.

PURPOSE: To determine the relationship between the bone formation-related functions of GPR126 and the structural asymmetry of spine in adolescent idiopathic scoliosis (AIS). METHODS: Vertebral body samples were obtained from 51 AIS patients during spinal surgery between October 2014 and November 2017, and the expression pattern of GPR126 in the convex/concave sides of AIS spine was identified by RT-qPCR. Next, we explored the bone formation-related functions of GPR126 by knocking down and overexpressing GPR126 in human mesenchymal stem cells (hMSC) and further performing osteogenic differentiation. We also applied overexpression of N-terminal fragments derived from GPR126 (GPR126-NTFs) and osteogenic differentiation experiments to determine the functional part of GPR126 in skeletal development. RESULTS: We provided evidence that GPR126 showed a marked convex/concave asymmetric expression in the spine of AIS. Further RNA detection found that exon6-included transcripts of GPR126 (GPR126-exon6in) were significantly higher expressed in the convex side of AIS patients. Knocking down of GPR126 accelerated ossification of hMSCs during osteogenic differentiation, and overexpression of GPR126-exon6in delayed this process. Overexpression of GPR126-NTFs revealed that NTF is a functional fragment and exon6-included NTF (NTF-exon6in) delayed ossification of hMSCs. CONCLUSION: Our findings indicated that GPR126-NTFs play a role in skeletal development, and the inclusion/exclusion of exon6 may regulate the bone formation-related functions of GPR126. The convex/concave asymmetric expression of GPR126-exon6in may be an important factor in abnormal bone formation of AIS. These slides can be retrieved under Electronic Supplementary Material.

Asymmetric expression of H19 and ADIPOQ in concave/convex paravertebral muscles is associated with severe adolescent idiopathic scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common paediatric spinal deformity. The etiology and pathology of AIS remain unexplained, and have been reported to involve a combination of genetic and epigenetic factors. Since paravertebral muscle imbalance plays an important role in the onset and progression of scoliosis, we aimed to investigate transcriptomic differences by RNA-seq and identify significantly differentially expressed transcripts in two sides of paravertebral muscle in AIS. METHODS: RNA-seq was performed on 5 pairs of paravertebral muscle from 5 AIS patients. Significantly differentially expressed transcripts were validated by quantitative reverse polymerase chain reaction. Gene expression difference was correlated to clinical characteristics. RESULTS: We demonstrated that ADIPOQ mRNA and H19 is significantly differentially expressed between two sides of paravertebral muscle, relatively specific in the context of AIS. Relatively low H19 and high ADIPOQ mRNA expression levels in concave-sided muscle are associated with larger spinal curve and earlier age at initiation. We identified miR-675-5p encoded by H19 as a mechanistic regulator of ADIPOQ expression in AIS. We demonstrated that significantly reduced CCCTC-binding factor (CCTF) occupancy in the imprinting control region (ICR) of the H19 gene in the concave-sided muscle contributes to down-regulated H19 expression. CONCLUSIONS: RNA-seq revealed transcriptomic differences between two sides of paravertebral muscle in AIS patients. Our findings imply that transcriptomic differences caused by epigenetic factors in affected individuals may account for the structural and functional imbalance of paravertebral muscle, which can expand our etiologic understanding of this disease.

Volumetric and Fatty Infiltration Imbalance of Deep Paravertebral Muscles in Adolescent Idiopathic Scoliosis.

BACKGROUND Several studies have described the differences in electromyographic activity and histological changes of paravertebral muscles in patients with adolescent idiopathic scoliosis (AIS). However, there is little knowledge about the muscle volumetric and fatty infiltration imbalance of patients with AIS. MATERIAL AND METHODS Thirty-four patients with AIS were evaluated with standardized anteroposterior (AP) and lateral standing films for the location and direction of the apex of scoliosis, coronal Cobb angle, apex vertebra translation, and thoracic kyphosis; and with magnetic resonance imaging (MRI) scan of the spine at the level of T4-L1. The muscle volume and fatty infiltration rate of bilateral deep paravertebral muscles at the level of upper end, apex, and lower end vertebra were measured. RESULTS All patients had major thoracic curve with apex of curves on the right side. The muscle volume on the convex side was larger relative to the concave side at the three levels, while the fatty infiltration rate was significantly higher on the concave side. The difference index of the muscle volume was significantly larger at the apex vertebra level than at the upper end vertebra level (p=0.002) or lower end vertebra level (p<0.001). The difference index of muscle volume correlated with apex vertebra translation (r=-0.749, p=0.032), and the difference index of fatty involution correlated with apex vertebra translation (r=0.727, p=0.041) and Cobb angle (r=0.866, p=0.005). CONCLUSIONS Our findings demonstrated significant imbalance of muscle volume and fatty infiltration in deep paravertebral muscles of AIS patients. Moreover, these changes affected different vertebra levels, with the most imbalance of muscle volume at the apex vertebra. We interpreted this as morphological changes corresponding with known altered muscle function of AIS.

External fixation versus open reduction and internal fixation for tibial pilon fractures: A meta-analysis based on observational studies.

PURPOSE: Tibial pilon fractures remain challenging for an orthopaedic surgeon to repair. External fixation (ExFix) and open reduction and internal fixation (ORIF) are two widely used methods for repairing tibial pilon fractures. However, conclusions of comparative studies regarding which method is superior are controversial. Our aim is to compare ORIF and ExFix and clarify which method is better in terms of reduction and union results and major complications. METHODS: A computerized research of MEDLINE, EMBASE, Springer, and Cochrane Library (before December 2014) for studies of any design comparing ORIF and ExFix was conducted. Weighted mean difference (WMD), risk ratio (RR) and corresponding 95% confidence intervals (CI) were used for esti- mating the effects of the two methods. Statistical analyses were done using Review Manager Version 5.2. RESULTS: Ten cohort studies and one randomized clinical trial were included in our ultimate analysis. And the analysis found no significant difference between the two methods in deep infection (p = 0.13), reduction (p = 0.11), clinical evaluation (p = 0.82), post-traumatic arthrosis (p = 0.87), and union time (p = 0.35). Besides, ExFix group was found to have a higher rate of superficial infection (p =0.001), malunion (p = 0.01) and nonunion (p = 0.02), but have a lower risk of unplanned hardware removal (p = 0.0002). CONCLUSIONS: We suggest that ORIF has a relatively lower incidence rate of superficial infection, malunion and nonunion, but a higher rate of unplanned hardware removal. No difference was found in deep infection, reduction, clinical evaluation, post-traumatic arthrosis and union time.

Spatial variability and source analysis of soil heavy metals: A case study of the key planting area of special agricultural products in Cangxi County, China.

Heavy metal pollution in farmland soil represents a considerable risk to ecosystems and human health, constituting a global concern. Focusing on a key area for the cultivation of special agricultural products in Cangxi County, we collected 228 surface soil samples. We analyzed the concentration, spatial distribution, and pollution levels of six heavy metals (Cr, Cu, Pb, Ni, Zn, and Hg) in the soil. Moreover, we investigated the sources and contribution rates of these heavy metals using Principal Component Analysis/Absolute Principal Component Scores (PCA/APCS) and Positive Matrix Factorization (PMF) models. Our findings indicate that none of the six metals exceeded the pollution thresholds for farmland soils. However, the mean concentrations of Cr and Ni surpassed the background levels of Sichuan Province. A moderate spatial correlation existed between Pb and Ni, attributable to both natural and anthropogenic factors, whereas Zn, Cu, Hg, and Cr displayed a strong spatial correlation, mainly due to natural factors. The spatial patterns of Cr, Cu, Zn, Pb, and Ni were similar, with higher concentrations in the northern and eastern regions and lower concentrations centrally. Hg's spatial distribution differed, exhibiting a broader range of lower values. The single pollution index evaluation showed that Cr and Ni were low pollution, and the other elements were no pollution. The average value of comprehensive pollution index is 0.994, and the degree of pollution is close to light pollution. Predominantly, higher pollution levels in the northern and eastern regions, lower around reservoirs. The PCA/APCS model identified two main pollution sources: agricultural traffic mixed source (65.2%) and natural parent source (17.2%). The PMF model delineated three sources: agricultural activities (32.59%), transportation (30.64%), and natural parent sources (36.77%). Comparatively, the PMF model proved more accurate and reliable, yielding findings more aligned with the study area's actual conditions.

A Genetic Variant of the ROBO3 Gene is Associated With Adolescent Idiopathic Scoliosis in the Chinese Population.

STUDY DESIGN: A case-control association study. OBJECTIVES: This study aimed to reveal whether mutations within roundabout receptor 3 ( ROBO3 ) gene were related to adolescent idiopathic scoliosis (AIS) in Chinese Han population and to investigate the functional role of ROBO3 in the pathogenesis and progression of AIS. SUMMARY OF BACKGROUND DATA: ROBO3 is essential for the regulation of hindbrain axonal cell migration and midline crossing. Studies have demonstrated that ROBO3 homozygous mutations are associated with horizontal gaze palsy with progressive scoliosis. However, whether and how ROBO3 contributed to the development of scoliosis remains unclear. MATERIALS AND METHODS: Whole exome sequencing was performed in 135 AIS patients and 267 healthy controls to evaluate the differences of single nucleotide polymorphism variants within ROBO3 . Then the identified variant of ROBO3 was genotyped in another cohort included 1140 AIS patients and 1580 controls. Moreover, paraspinal muscles were collected from 39 AIS patients and 45 lumbar disk herniation patients for the measurement of ROBO3 mRNA expression. The χ 2 test, Fisher exact test or the Student t test were used to compare intergroup data. Pearson correlation was used to determine the association between ROBO3 expression and clinical phenotypes. RESULTS: A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS through exome sequencing. The genotyping cohort demonstrated a higher frequency of allele A in AIS patients compared to controls (7.89% vs . 4.30%, P <0.001, odds ratio=1.87). In addition, the expression of ROBO3 in paraspinal muscles was inversely correlated with the Cobb angle ( P =0.043, r2 =0.1059). CONCLUSION: A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS. The reduced expression of ROBO3 could result in the progression of curve magnitude in patients with AIS. Further studies are needed to verify the functional role of ROBO3 in the development of AIS. LEVEL OF EVIDENCE: Level III.

Deubiquitinase USP13 regulates glycolytic reprogramming and progression in osteosarcoma by stabilizing METTL3/m6A/ATG5 axis.

Reprogramming metabolism is a hallmark of cancer cells for rapid progression. However, the detailed functional role of deubiquitinating enzymes (DUBs) in tumor glycolytic reprogramming is still unknown and requires further investigation. USP13 was found to upregulate in osteosarcoma (OS) specimens and promote OS progression through regulating aerobic glycolysis. Interestingly, the m6A writer protein, METTL3, has been identified as a novel target of USP13. USP13 interacts with, deubiquitinates, and therefore stabilizes METTL3 at K488 by removing K48-linked ubiquitin chains. Since METTL3 is a well-known m6A writer and USP13 stabilizes METTL3, we further found that USP13 increased global m6A abundance in OS cells. The results of RNA sequencing and methylated RNA immunoprecipitation sequencing indicated METTL3 could bind to m6A-modified ATG5 mRNA, which is crucial for autophagosome formation, and inhibit ATG5 mRNA decay on an IGF2BP3 dependent manner, thereby promoting autophagy and the autophagy-associated malignancy of OS. Using a small-molecule inhibitor named Spautin-1 to pharmacologically inhibit USP13 induced METTL3 degradation and exhibited significant therapeutic efficacy both in vitro and in vivo. Collectively, our study results indicate that USP13 promotes glycolysis and tumor progression in OS by stabilizing METTL3, thereby stabilizing ATG5 mRNA and facilitating autophagy in OS. Our findings demonstrate the role of the USP13-METTL3-ATG5 cascade in OS progression and show that USP13 is a crucial DUB for the stabilization of METTL3 and a promising therapeutic target for treating OS.

Association between gut microbiota and bone metabolism: Insights from bibliometric analysis.

Gut microbiota has been reported to participate in bone metabolism. However, no article has quantitatively and qualitatively analyzed this crossing field. The present study aims to analyze the current international research trends and demonstrate possible hotspots in the recent decade through bibliometrics. We screened out 938 articles meeting the standards from 2001 to 2021 in the Web of Science Core Collection database. Bibliometric analyses were performed and visualized using Excel, Citespace, and VOSviewer. Generally, the annual number of published literatures in this field shows an escalating trend. The United States has the largest number of publications, accounting for 30.4% of the total. Michigan State University and Sichuan University have the largest number of publications, while Michigan State University has the highest average number of citations at 60.00. Nutrients published 49 articles, ranking first, while the Journal of Bone and Mineral Research had the highest average number of citations at 13.36. Narayanan Parameswaran from Michigan State University, Roberto Pacifici from Emory University, and Christopher Hernandez from Cornell University were the three professors who made the largest contribution to this field. Frequency analysis showed that inflammation (148), obesity (86), and probiotics (81) are keywords with the highest focus. Moreover, keywords cluster analysis and keywords burst analysis showed that "inflammation", "obesity", and "probiotics" were the most researched topics in the field of gut microbiota and bone metabolism. Scientific publications related to gut microbiota and bone metabolism have continuously risen from 2001 to 2021. The underlying mechanism has been widely studied in the past few years, and factors affecting the alterations of the gut microbiota, as well as probiotic treatment, are emerging as new research trends.

Comparison of surgical outcomes of C1-2 fusion surgery between O-arm-assisted operation and C-arm assisted operation in children with atlantoaxial rotatory fixation.

Objective: Placement of the pedicle screw is technically challenging during C1-2 fusion surgery in children and different intraoperative image-guided systems have been developed to reduce the risk of screw malposition. The purpose of the present study was to compare surgical outcomes between C-arm fluoroscopy and O-arm navigated pedicle screw placement in the treatment of atlantoaxial rotatory fixation in children. Methods: We retrospectively evaluated charts of all consecutive children with atlantoaxial rotatory fixation who underwent C-arm fluoroscopy or O-arm navigated pedicle screw placement from April 2014 to December 2020. Outcomes including operative time, estimated blood loss (EBL), accuracy of screw placement (Neo's classification) and completed fusion time were evaluated. Results: A total of 340 screws were placed in 85 patients. The accuracy of screw placement of the O-arm group was 97.4%, which was significantly higher than that of the C-arm group (91.8%). Both groups had satisfied bony fusion (100%). Statistical significance (230.0 ± 34.6 ml for the C-arm group and 150.6 ± 47.3 ml for the O-arm group, p < 0.05) was observed with respect to the median blood loss. There were no statistically significant difference (122.0 ± 16.5 min for the C-arm group and 110.0 ± 14.4 min for the O-arm group, p = 0.604) with respect to the median operative time. Conclusion: O-arm-assisted navigation allowed more accurate screw placement and less intraoperative blood loss. Both groups had satisfied bony fusion. O-arm navigation did not prolong the operative time despite the time required for setting and scanning.

Rational polyelectrolyte nanoparticles endow preosteoclast-targeted siRNA transfection for anabolic therapy of osteoporosis.

Targeted transfection of siRNA to preosteoclasts features the potential of anti-osteoporosis, yet challenge arises from the development of satisfied delivery vehicles. Here, we design a rational core-shell nanoparticle (NP) composed of cationic and responsive core for controlled load and release of small interfering RNA (siRNA) and compatible polyethylene glycol shell modified with alendronate for enhanced circulation and bone-targeted delivery of siRNA. The designed NPs perform well on transfection of an active siRNA (siDcstamp) that interferes Dcstamp mRNA expression, leading to impeded preosteoclast fusion and bone resorption, as well as promoted osteogenesis. In vivo results corroborate the abundant siDcstamp accumulation on bone surfaces and the enhanced trabecular bone mass volume and microstructure in treating osteoporotic OVX mice by rebalancing bone resorption, formation, and vascularization. Our study validates the hypothesis that satisfied transfection of siRNA enables preserved preosteoclasts that regulate bone resorption and formation simultaneously as potential anabolic treatment for osteoporosis.

In Situ Enzymatic Reaction Generates Magnesium-Based Mineralized Microspheres with Superior Bioactivity for Enhanced Bone Regeneration.

Bone is a naturally mineralized tissue with a remarkable hierarchical structure, and the treatment of bone defects remains challenging. Microspheres with facile features of controllable size, diverse morphologies, and specific functions display amazing potentials for bone regeneration. Herein, inspired by natural biomineralization, a novel enzyme-catalyzed reaction is reported to prepare magnesium-based mineralized microspheres. First, silk fibroin methacryloyl (SilMA) microspheres are prepared using a combination of microfluidics and photo-crosslinking. Then, the alkaline phosphatase (ALP)-catalyzed hydrolysis of adenosine triphosphate (ATP) is successfully used to induce the formation of spherical magnesium phosphate (MgP) in the SilMA microspheres. These SilMA@MgP microspheres display uniform size, rough surface structure, good degradability, and sustained Mg2+ release properties. Moreover, the in vitro studies demonstrate the high bioactivities of SilMA@MgP microspehres in promoting the proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Transcriptomic analysis shows that the osteoinductivity of SilMA@MgP microspheres may be related to the activation of the PI3K/Akt signaling pathway. Finally, the bone regeneration enhancement units (BREUs) are designed and constructed by inoculating BMSCs onto SilMA@MgP microspheres. In summary, this study demonstrates a new biomineralization strategy for designing biomimetic bone repair materials with defined structures and combination functions.

Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis.

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)-specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC-specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2-deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.

Sectional Correction Technique in Dystrophic Scoliosis Secondary to Neurofibromatosis Type 1: A Comparison with Traditional 2-Rod Correction Technique.

OBJECTIVE: The purpose of this study was to compare the traditional 2-rod correction technique with the sectional correction technique in terms of radiographic results and clinical outcomes for patients with dystrophic scoliosis caused by neurofibromatosis type 1 (NF1). METHODS: From May 2015 to April 2018, 53 patients with dystrophic scoliosis caused by NF1 underwent 1-stage posterior corrective surgery. Patients were separated into 2 groups based on technique: the sectional correction technique (SC group) and the traditional 2-rod technique (TT group). Before surgery and at the final follow-up, the demographic information, radiographic parameters, and clinical outcomes were compared between the groups using independent-sample t tests. RESULTS: The SC group consisted of 24 patients, while the TT group consisted of 29 patients. Patients in the SC group showed a higher coronal balance distance after the operation (8.3 ± 8.2 mm vs. 16.2 ± 8.8 mm, P = 0.002) and at the final follow-up (9.5 ± 9.3 mm vs. 19.3 ± 10.1 mm, P < 0.0001). At the last follow-up, the loss of correction in the SC group was 2.2 ± 0.9 and 2.1 ± 0.7 in the coronal and sagittal planes, respectively, and these values were significantly lower than those in the TT group (5.3 ± 1.6 in the coronal plane and 4.5 ± 1.9 in the sagittal plane, both P < 0.05). The SC group had better improvement based on appearance and satisfaction score at the final follow-up. CONCLUSIONS: The sectional correction technique using a concave domino connector can restore coronal imbalance and reduce the risk of implant failure.