Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice.

Endplate sclerosis is a notable aspect of spine degeneration or aging, but the mechanisms remain unclear. Here, we report that senescent macrophages accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging male mouse model. Specifically, knockout of cdkn2a (p16) in macrophages abrogates LSI or aging-induced angiogenesis and sclerosis in the endplates. Furthermore, both in vivo and in vitro studies indicate that IL-10 is the primary elevated cytokine of senescence-related secretory phenotype (SASP). Mechanistically, IL-10 increases pSTAT3 in endothelial cells, leading to pSTAT3 directly binding to the promoters of Vegfa, Mmp2, and Pdgfb to encourage their production, resulting in angiogenesis. This study provides information on understanding the link between immune senescence and endplate sclerosis, which might be useful for therapeutic approaches.

Study on the relationship between tea polyphenols alleviating osteoporosis and the changes of microorganism-metabolite-intestinal barrier.

Tea polyphenols are known to alleviate osteoporosis; however, the role of intestinal flora in this process has not been studied. This research employed 16s rRNA sequencing and non-targeted metabonomics to investigate the potential link between osteoporosis mitigation and changes in intestinal flora. MicroCT and tissue staining results demonstrated that tea polyphenols improved bone microstructure, modulated bone metabolism, and significantly alleviated osteoporosis. The administration of tea polyphenols led to alterations in the intestinal flora's composition, marked by increased abundance of Firmicutes and Lactobacillus and decreased prevalence of Bacteroidetes and Bacteroides. Concurrently, the levels of serum metabolites such as Spermidine and 5,6-Dihydrouracil, associated with intestinal microorganisms, underwent significant changes. These variations in intestinal flora and metabolites are closely linked to bone metabolism. Furthermore, tea polyphenols partially repaired intestinal barrier damage, potentially due to shifts in intestinal flora and their metabolites. Overall, our findings suggest that tea polyphenol intervention modifies the intestinal flora and serum metabolites in osteoporotic mice, which could contribute to the repair of intestinal barrier damage and thereby mitigate osteoporosis. This discovery aids in elucidating the mechanism behind tea polyphenols' osteoporosis-relieving effects.

Adipose mesenchymal stem cells-derived exosomes alleviate osteoarthritis by transporting microRNA -376c-3p and targeting the WNT-beta-catenin signaling axis.

Osteoarthritis (OA), one of the major diseases afflicting the elderly, is a type of degenerative joint disease related to cartilage and synovium. This study aimed to clarify the role and mechanism of adipose mesenchymal stem cell (ADSC)-derived exosomes (Exos) in OA-induced chondrocyte degradation and synovial hyperplasia, thus improving the quality of life of patients. The rat OA model, chondrocytes, synovial fibroblast models and immunofluorescence were applied to observe the in vivo and in vitro functions of human ADSC (hADSC)-derived Exos in OA and its possible regulatory signaling pathways. Bioinformatics software and luciferase reporter assay were carried out to verify the mechanism of microRNA-376c-3p (miR-376c-3p) in hADSC-derived Exos in OA in vitro. Moreover, Safranine O-Fast Green Cartilage staining, Masson staining, immunohistochemistry and immunofluorescence were conducted to verify the role of miR-376c-3p in hADSC-derived Exos in OA in vivo. hADSC-derived Exos mitigated OA-induced chondrocyte degradation and synovial fibrosis both in vivo and in vitro models by repressing the WNT-beta-catenin signaling pathway. For the mechanism exploration in vitro, miR-376c-3p was raised in hADSC-derived Exos and mediated the fibrosis of synovial fibroblasts in OA, and miR-376c-3p targeted the 3'-untranslated region of WNT3 or WNT9a. Meanwhile, the in vivo experiments also corroborated that the miR-376c-3p in hADSC-derived Exos mitigated OA-induced chondrocyte degradation and synovial fibrosis. MiR-376c-3p in hADSC-derived Exos repressed the WNT-beta-catenin pathway by targeting WNT3 or WNT9a, and then mitigating OA-induced chondrocyte degradation and synovial fibrosis, thereby providing theoretical basis for clinical implementation of treatment.

The preliminary outcomes of vertebral body tethering in treating adolescent idiopathic scoliosis: a systematic review.

PURPOSE: VBT is a novel alternative to spinal fusion surgery to treat skeletally immature AIS and was approved to correct idiopathic scoliosis in August 2019 by US Federal Drug Administration (FDA). To systemically review the preliminary outcomes of vertebral body tethering (VBT) in treating adolescent idiopathic scoliosis. METHODS: The electronic databases PubMed, EMBASE, and Web of Science were queried up to January 2022 for articles regarding VBT. Basic characteristics of patients, changes of radiographic parameters in coronal and sagittal planes, and clinical outcomes of surgical treatment of VBT including complication and revision rates were summarized. RESULTS: Twenty five studies met the inclusion criteria. Most studies (23/25) included patients with only skeletal immaturity. The average % correction of the main/tethered curve at final follow-up, and % correction of thoracic kyphosis at final follow-up were reported to be 15.6-106.5% and - 31.8 to 20.0%, respectively. The most common complications for VBT were tether breakage (n = 145;21.3%), pulmonary complications (n = 49; 6.9%), and overcorrection (n = 30; 4.2%). The revision rate was 13.1%. CONCLUSION: VBT could effectively and safely correct spinal deformity in skeletally immature patients with AIS and preserve the motion and growth of the spine. However, VBT has a relatively high complication and revision rates. Therefore, surgeons should cautiously consider VBT for treating AIS. Future research efforts are needed to lower the complication and revision rates. Whatever, VBT is still in its infancy and may have a promising future as a non-fusion solution for AIS.

Association Between Gut Microbiota and Osteoarthritis: A Review of Evidence for Potential Mechanisms and Therapeutics.

Osteoarthritis (OA) is a multifactorial joint disease characterized by degeneration of articular cartilage, which leads to joints pain, disability and reduced quality of life in patients with OA. Interpreting the potential mechanisms underlying OA pathogenesis is crucial to the development of new disease modifying treatments. Although multiple factors contribute to the initiation and progression of OA, gut microbiota has gradually been regarded as an important pathogenic factor in the development of OA. Gut microbiota can be regarded as a multifunctional "organ", closely related to a series of immune, metabolic and neurological functions. This review summarized research evidences supporting the correlation between gut microbiota and OA, and interpreted the potential mechanisms underlying the correlation from four aspects: immune system, metabolism, gut-brain axis and gut microbiota modulation. Future research should focus on whether there are specific gut microbiota composition or even specific pathogens and the corresponding signaling pathways that contribute to the initiation and progression of OA, and validate the potential of targeting gut microbiota for the treatment of patients with OA.

The Role of Intestinal Flora in the Regulation of Bone Homeostasis.

Intestinal flora located within the intestinal tract comprises a large number of cells, which are referred to as the second gene pool of the human body and form a complex symbiotic relationship with the host. The knowledge of the complex interaction between the intestinal flora and various life activities of the host is a novel and rapidly expanding field. Recently, many studies are being conducted on the relationship between the intestinal flora and bone homeostasis and indicate that the intestinal flora can regulate bone homeostasis via the host immune, metabolic, and endocrine systems. What's more, based on several clinical and preclinical pieces of evidence, changing the composition and function of the host intestinal flora through the application of probiotics, prebiotics, and fecal microbiota transplantation is being considered to be a potential novel target for the regulation of bone homeostasis. Here, we searched relevant literature and reviewed the role of the intestinal flora in the regulation of bone homeostasis and its modulating interventions.

Gut Microbiome Reveals Specific Dysbiosis in Primary Osteoporosis.

Object: Primary osteoporosis (PO) is the most common bone disease, which is characterized by decreased bone mass, damage of bone tissue microstructure, increased bone fragility, and is prone to fracture. Gut microbiome may be involved in bone metabolism of PO through gut-brain axis regulation of immune system and endocrine system, however, the specific mechanism is still unclear. The purpose of this study was to characterize the gut microbiome of patients with PO and its possible role in the occurrence and development of the disease. Methods: Fecal samples were collected from 48 PO patients and 48 healthy controls (HC). The composition of gut microbiome community was analyzed by 16s rDNA amplification sequencing, and the difference of gut microbiome composition between PO patients and HC individuals was compared. PICRUSt was also used to predict the biological function of gut microbiome in patients with PO, and to explore its possible role in the occurrence and development of this disease. The classification model is constructed by random forest algorithm so as to screen the key biomarkers. Result: The diversity of gut microorganisms in PO patients was significantly higher than that in HC group (p < 0.05) and there was significant difference in microbial composition in PO group. The abundance of Dialister (0.036 vs. 0.004, p < 0.001) and Faecalibacterium (0.331 vs. 0.132, p < 0.001) were significantly enriched which were the key flora related to PO. Although no significant correlation between bone mineral density and the richness of microbial communities are found, PICRUST results show that there are a wide range of potential pathways between gut microbiome and PO patients, including genetic information processing, metabolism, environmental information processing, cellular processes, human diseases, and organic systems. Notably, the discriminant model based on dominant microflora can effectively distinguish PO from HC (AUC = 93.56). Conclusions: The findings show that PO is related to the change of gut microbiome, especially the enriched Dialister and Faecalibacterium genera, which give new clues to understand the disease and provide markers for the diagnosis and new strategies for intervention treatment of the disease.

Systematic construction and validation of an immune prognostic model for lung adenocarcinoma.

Lung adenocarcinoma (LUAD), the most common non-small-cell lung cancer, is characterized by a dense lymphocytic infiltrate, which indicates that the immune system plays an active role in the development and growth of this cancer. However, no investigations to date have proposed robust models for predicting survival outcome for patients with LUAD in terms of tumour immunology. A total of 761 LUAD patients were included in this study, in which the database of The Cancer Genome Atlas (TCGA) was utilized for discovery, and the Gene Expression Omnibus (GEO) database was utilized for validation. Bioinformatics analysis and R language tools were utilized to construct an immune prognostic model and annotate biological functions. Lung adenocarcinoma showed a weakened immune phenotype compared with adjacent normal tissues. Immune-related gene sets were profiled, an immune prognostic model based on 2 immune genes (ANLN and F2) was developed with the TCGA database to distinguish cases as having a low or high risk of unfavourable prognosis, and the model was verified with the GEO database. The model was prognostically significant in stratified cohorts, including stage I-II, stage III-IV and epidermal growth factor receptor (EGFR) mutant subsets, and was considered to be an independent prognostic factor for LUAD. Furthermore, the low- and high-risk groups showed marked differences in tumour-infiltrating leucocytes, tumour mutation burden, aneuploidy and PD-L1 expression. In conclusion, an immune prognostic model was proposed for LUAD that is capable of independently identifying patients at high risk for poor survival, suggesting a relationship between local immune status and prognosis.

Risk factors for upper adjacent segment degeneration after multi-level posterior lumbar spinal fusion surgery.

BACKGROUND: Posterior lumbar spinal fusion has been widely used in degenerative lumbar stenosis, but adjacent segment degeneration (ASD) was common. Researchers have found many risk factors for ASD after one or two levels of surgery, but few clinical studies focused on multi-level surgery. The purpose of this study was to clarify risk factors for upper ASD after multi-level posterior lumbar spinal fusion. METHODS: A retrospective study was performed on the clinical data of 71 patients with degenerative lumbar stenosis who underwent multi-level (at least 3 levels) posterior lumbar spinal fusion from January 2013 to December 2016. Two groups were divided according to lamina and posterior ligamentous complex (PLC) maintenance of proximal fixed vertebrae in surgery. In the 22 patients of group A, the proximal fixed vertebral lamina and PLC were not resected, and in the 49 patients of group B, the proximal fixed vertebral lamina and PLC were resected completely. Age, sex, body mass index (BMI), number of fixed vertebrae and fused levels, spinopelvic parameters, coronal Cobb angle, and modified Pfirrmann grading system were measured for each patient. A Cox proportional hazards model was used to analyze risk factors for upper ASD. RESULTS: No symptomatic ASD was found during the follow-up period. Patients who underwent proximal fixed vertebral lamina and PLC resection had a significantly higher percentage of radiographic ASD (P = 0.042). The Cox proportional hazards model showed that age, sex, BMI, preoperative lumbar lordosis, sacral slope, pelvic tilt, coronal Cobb angle, number of fixed vertebrae, and interbody fusion levels had no significant differences for radiographic ASD. But a preoperative modified Pfirrmann grade higher than 3, a high degree of preoperative pelvic incidence, and more decompressed levels had statistical significance (P = 0.024, 0.041, and 0.008, respectively). CONCLUSIONS: A preoperative modified Pfirrmann grade higher than 3, a high degree of preoperative pelvic incidence, and more decompressed levels might be risk factors for upper radiographic ASD after multi-level posterior lumbar spinal fusion surgery.

Long-term real-time tracking live stem cells/cancer cells in vitro/in vivo through highly biocompatible photoluminescent poly(citrate-siloxane) nanoparticles.

Long-term live cell tracking is desirable and necessary to understand the dynamics and complexity of biological interactions in stem cells and cancer cells. Conventional live cells fluorescence trackers are generally non-degradable and are showing increased toxicity concerns during the long-term application. Previously we developed biodegradable fluorescent poly(citrate)-based hybrid elastomers for bone regeneration applications. Here, we fabricated the photoluminescent poly(citrate-siloxane) nanoparticles (PCSNPs) through an oil/water emulsion method and demonstrated their long-term live stem cells/cancer cells imaging applications. PCSNPs showed a uniform size distribution (mean diameter 120 nm) and highly stable dispersability (above 30 days) in various physiological medium, as well as excellent fluorescent properties and photostability. PCSNPs possess excellent cellular biocompatibility, which could be efficiently internalized by cells and selectively image the cell lysosome with a high photostability. Compared with commercial Cell Tracker™ Green and Cell Tracker™ Red, the adipose-derived mesenchymal stem cells or human hepatoma cells were stably labeled by PCSNPs for over 14 days as they grew and developed (7 passages). Additionally, PCSNPs efficiently tracked cells up to 7 days in vivo through a non-invasively way compared with 1 day of commercial tracker. This study demonstrates an important strategy to design biodegradable multifunctional delivery platforms for biomedical applications such as long-term bioimaging.

LncRNA GAS5 Overexpression Reverses LPS-Induced Inflammatory Injury and Apoptosis Through Up-Regulating KLF2 Expression in ATDC5 Chondrocytes.

BACKGROUND/AIMS: Osteoarthritis (OA) is the most frequently occurring joint disease and characterized by degeneration of cartilage. As the unique cell type in cartilage, chondrocytes play a crucial role during OA. Our study explored the influence of long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) on lipopolysaccharides (LPS)-induced injury in ATDC5 cells. METHODS: Cell viability, apoptosis and expression of inflammatory cytokines were all assessed to evaluate LPS-induce inflammatory injury. Expression of GAS5 in LPS-induced cells was evaluated by qRT-PCR. After cell transfection, effect of abnormally expressed GAS5 on LPS-induced inflammatory injury was determined. Then, the possible target of GAS5 was screened by bioinformatics and verified by qRT-PCR and luciferase activity assay. Together, whether aberrant expression of target gene affected the modulation of GAS5 in LPS-induced inflammatory injury was also assessed. Finally, the influences of aberrant expressed Kruppel-like factor 2 (KLF2) on nuclear factor κB (NF-κB) and Notch pathways were detected by Western blot analysis. RESULTS: LPS reduced cell viability and promoted cell apoptosis and secretion of inflammatory cytokines, along with down-regulation of GAS5. LPS-induced injury was alleviated by GAS5 overexpression while was exacerbated by GAS5 silence. KLF2 was predicted and verified as a target of GAS5, and GAS5 functioned through regulating expression of KLF2. Besides, aberrant expression of KLF2 regulated expressions of key kinases involved in the NF-κB and Notch pathways. CONCLUSION: GAS5 might ameliorate LPS-induced inflammatory injury in ATDC5 chondrocytes by inhibiting the NF-κB and Notch signaling pathways.

Europium Doped Monodispersed Bioactive Glass Nanoparticles Regulate the Osteogenic Differentiation of Human Marrow Mesenchymal Stem Cells.

The osteogenic differentiation of marrow mesenchymal stem cells (MSCs) is very important for bone tissue regeneration. Nanoscale biomaterials have shown promising effect on the osteogenic differentiation of MSCs. In this study, we investigate the effect of europium doped bioactive glass nanoparticles (BGNEu) on the osteogenic differentiation of human MSCs (hMSCs). The cell attachment and proliferation, alkaline phosphatase activity (ALP), collagen I secretion (COL I) and osteoblasts-related gene expressions (Alp, Col I), Osteopontin (Opn), runt-related transcription factor 2 (Runx2) were studied after culture with BGNEu (1%, 3%, 5% in mol%) with and without osteogenic inducing factors. The results showed that BGNEu3 significantly enhanced hMSCs osteogenic differentiation (ALP activity and COL I secretion) by activating osteogenic genes expressions (Alp, Col I, Opn, Runx2) in absence of osteogenic inducing factor. Enhanced osteogenic genes levels were also found by combining BGNEu3 and osteogenic inducing factors. This study may provide an alternative strategy in designing novel bioactive biomaterials with osteogenic inducing ability for bone tissue regeneration.

Biodegradable, Biomimetic Elastomeric, Photoluminescent, and Broad-Spectrum Antibacterial Polycitrate-Polypeptide-based Membrane toward Multifunctional Biomedical Implants.

Current biomedical membranes in guided tissue regeneration applications are almost nonbiodegradable or deficient in functionality. The development of biodegradable biomaterials with multifunctional properties including biomimetic elastomeric behavior, self-anti-infection, noninvasive monitoring, and good biocompatibility has attracted much attention. Here, we report a biodegradable and biocompatible polycitrate-(ε-polypeptide)-based (PCE) biomedical elastomer membrane with intrinsic broad-spectrum antibacterial activity and photoluminescent capacity for multifunctional guided tissue regenerative applications. PCE showed highly elastomeric mechanical behavior (∼300% elongation and ∼100% recovery) and biomimetic mechanical properties against several native tissues. PCE film also possessed highly efficient broad-spectrum antibacterial activity in vitro and in vivo. The inherent photoluminescent properties of PCE film endowed their real-time noninvasive monitoring capacity in vivo. Owing to the biocompatible structure (polycitrate and natural polypeptide), PCE film demonstrated significantly high cytocompatibility and hemocompatibility in vitro and low inflammatory response in vivo. Our study may provide a new strategy to design next generation multifunctional biodegradable biomedical implant membranes for smart guided tissue regenerative medicine applications.

Comparison of pedicle screw-based dynamic stabilization and fusion surgery in the treatment of radiographic adjacent-segment degeneration: a retrospective analysis of single L5-S1 degenerative spondylosis covering 4 years.

OBJECTIVE Pedicle screw-based dynamic spinal stabilization systems (PDSs) were devised to decrease, theoretically, the risk of long-term complications such as adjacent-segment degeneration (ASD) after lumbar fusion surgery. However, to date, there have been few studies that fully proved that a PDS can reduce the risk of ASD. The purpose of this study was to examine whether a PDS can influence the incidence of ASD and to discuss the surgical coping strategy for L5-S1 segmental spondylosis with preexisting L4-5 degeneration with no related symptoms or signs. METHODS This study retrospectively compared 62 cases of L5-S1 segmental spondylosis in patients who underwent posterior lumbar interbody fusion (n = 31) or K-Rod dynamic stabilization (n = 31) with a minimum of 4 years' follow-up. The authors measured the intervertebral heights and spinopelvic parameters on standing lateral radiographs and evaluated preexisting ASD on preoperative MR images using the modified Pfirrmann grading system. Radiographic ASD was evaluated according to the results of radiography during follow-up. RESULTS All 62 patients achieved remission of their neurological symptoms without surgical complications. The Kaplan-Meier curve and Cox proportional-hazards model showed no statistically significant differences between the 2 surgical groups in the incidence of radiographic ASD (p > 0.05). In contrast, the incidence of radiographic ASD was 8.75 times (95% CI 1.955-39.140; p = 0.005) higher in the patients with a preoperative modified Pfirrmann grade higher than 3 than it was in patients with a modified Pfirrmann grade of 3 or lower. In addition, no statistical significance was found for other risk factors such as age, sex, and spinopelvic parameters. CONCLUSIONS Pedicle screw-based dynamic spinal stabilization systems were not found to be superior to posterior lumbar interbody fusion in preventing radiographic ASD (L4-5) during the midterm follow-up. Preexisting ASD with a modified Pfirrmann grade higher than 3 was a risk factor for radiographic ASD. In the treatment of degenerative diseases of the lumbosacral spine, the authors found that both of these methods are feasible. Also, the authors believe that no extra treatment, other than observation, is needed for preexisting degeneration in L4-5 without any clinical symptoms or signs.

HMGB1 Is Involved in the Protective Effect of the PPAR α Agonist Fenofibrate against Cardiac Hypertrophy.

High mobility group box 1 (HMGB1) is a ubiquitous nuclear DNA-binding protein whose function is dependent on its cellular location. Extracellular HMGB1 is regarded as a delayed mediator of proinflammatory cytokines for initiating and amplifying inflammatory responses, whereas nuclear HMGB1 has been found to prevent cardiac hypertrophy and heart failure. Because fenofibrate, a peroxisome proliferator-activated receptor α (PPAR α ) agonist, has shown both protective effects against cardiac hypertrophy and inhibitory effects against inflammation, the potential modulation of HMGB1 expression and secretion by fenofibrate is of great interest. We herein provide evidence that fenofibrate modulates basal and LPS-stimulated HMGB1 expression and localization in addition to secretion of HMGB1 in cardiomyocytes. In addition, administration of fenofibrate to mice prevented the development of cardiac hypertrophy induced by thoracic transverse aortic constriction (TAC) while increasing levels of nuclear HMGB1. Altogether, these data suggest that fenofibrate may inhibit the development of cardiac hypertrophy by regulating HMGB1 expression, which provides a new potential strategy to treat cardiac hypertrophy.

Effects of PGE2 EP3/EP4 receptors on bladder dysfunction in mice with experimental autoimmune encephalomyelitis.

To investigate the expression of four subtypes of PGE2 E-prostanoid (EP) receptors (EP1-EP4) and the effects of EP3/EP4 on bladder dysfunction in a new neurogenic bladder model induced by experimental autoimmune encephalomyelitis (EAE), the mouse model of EAE was induced using a previously established method, and bladder function in mice with different defined levels of neurological impairment was then examined, including micturition frequencies and voiding weight. Bladders were then harvested for analysis of EP receptor expression by Western blot. Activities of agonists/antagonists of EP3 and EP4 receptors as well as PGE2 were also evaluated at different stages of EAE. The results showed that EAE mice developed profound bladder dysfunction characterized by significantly increased micturition and significantly decreased urine output per micturition. EAE-induced upregulation of EP3 and EP4 receptors in the bladder was accompanied by bladder dysfunction. However, EAE had no significant effect on EP1 and EP2 receptors. Moreover, PGE2 and agonists/antagonists of EP3 and EP4 receptors significantly affected bladder dysfunction in EAE mice. Thus, we believe that EAE mice are useful for investigations of the neurogenic bladder. In addition, EP3 and EP4 receptors play a role in EAE-induced bladder dysfunction, providing us with a new target for the treatment of neurogenic bladders.