Tissue engineering strategies hold promise for the repair of articular cartilage injury.

Articular cartilage damage and wear can result in cartilage degeneration, ultimately culminating in osteoarthritis. Current surgical interventions offer limited capacity for cartilage tissue regeneration and offer only temporary alleviation of symptoms. Tissue engineering strategies are increasingly recognized as promising modalities for cartilage restoration. Currently, various biological scaffolds utilizing tissue engineering materials are extensively employed in both fundamental and clinical investigations of cartilage repair. In order to optimize the cartilage repair ability of tissue engineering scaffolds, researchers not only optimize the structure and properties of scaffolds from the perspective of materials science and manufacturing technology to enhance their histocompatibility, but also adopt strategies such as loading cells, cytokines, and drugs to promote cartilage formation. This review provides an overview of contemporary tissue engineering strategies employed in cartilage repair, as well as a synthesis of existing preclinical and clinical research. Furthermore, the obstacles faced in the translation of tissue engineering strategies to clinical practice are discussed, offering valuable guidance for researchers seeking to address these challenges.

Sirt1: An Increasingly Interesting Molecule with a Potential Role in Bone Metabolism and Osteoporosis.

Osteoporosis (OP) is a common metabolic bone disease characterized by low bone mass, decreased bone mineral density, and degradation of bone tissue microarchitecture. However, our understanding of the mechanisms of bone remodeling and factors affecting bone mass remains incomplete. Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase that regulates a variety of cellular metabolisms, including inflammation, tumorigenesis, and bone metabolism. Recent studies have emphasized the important role of SIRT1 in bone homeostasis. This article reviews the role of SIRT1 in bone metabolism and OP and also discusses therapeutic strategies and future research directions for targeting SIRT1.

TRPV Channels in Osteoarthritis: A Comprehensive Review.

Osteoarthritis (OA) is a debilitating joint disorder that affects millions of people worldwide. Despite its prevalence, our understanding of the underlying mechanisms remains incomplete. In recent years, transient receptor potential vanilloid (TRPV) channels have emerged as key players in OA pathogenesis. This review provides an in-depth exploration of the role of the TRPV pathway in OA, encompassing its involvement in pain perception, inflammation, and mechanotransduction. Furthermore, we discuss the latest research findings, potential therapeutic strategies, and future directions in the field, shedding light on the multifaceted nature of TRPV channels in OA.

Gut-bone axis research: unveiling the impact of gut microbiota on postmenopausal osteoporosis and osteoclasts through Mendelian randomization.

Background: Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known as the gut-bone axis, has garnered widespread attention. Methods: We employed a two-sample Mendelian randomization approach to assess the associations between gut microbiota with osteoclasts and postmenopausal osteoporosis, respectively. Single nucleotide polymorphisms associated with the composition of gut microbiota were used as instrumental variables. By analyzing large-scale multi-ethnic GWAS data from the international MiBioGen consortium, and combining data from the eQTLGen consortium and the GEFOS consortium, we identified microbiota related to osteoclasts and postmenopausal osteoporosis. Key genes were further identified through MAGMA analysis, and validation was performed using single-cell data GSE147287. Results: The outcomes of this study have uncovered significant associations within the gut microbiome community, particularly with the Burkholderiales order, which correlates with both an increase in osteoclasts and a reduced risk of postmenopausal osteoporosis. with an odds ratio (OR) of 0.400, and a P-value of 0.011. Further analysis using single-cell data allowed us to identify two key genes, FMNL2 and SRBD1, that are closely linked to both osteoclasts and osteoporosis. Conclusion: This study utilizing Mendelian randomization and single-cell data analysis, provides new evidence of a causal relationship between gut microbiota and osteoclasts, as well as postmenopausal osteoporosis. It was discovered that the specific microbial group, the Burkholderiales order, significantly impacts both osteoporosis and osteoclasts. Additionally, key genes FMNL2 and SRBD1 were identified, offering new therapeutic strategies for the treatment of postmenopausal osteoporosis.

IL-16 Mediates the Effect of Circulating Metabolites on Postmenopausal Osteoporosis: A Two-Step, Multivariable Mendelian Randomization Study.

Objectives: This study aimed to explore the relationship between circulating metabolites and postmenopausal osteoporosis (PMOP) and to assess the mediating role of inflammatory factors. Methods: Utilizing summary-level data from genome-wide association studies (GWAS) and employing a Mendelian Randomization approach, a two-sample MR analysis was conducted to assess the relationship between circulating metabolites and PMOP. Additionally, a two-step MR was used to quantify the mediating impact of inflammatory factors on the effect of circulating metabolites on PMOP. Results: The results revealed a significant association between certain metabolites and the risk of PMOP, notably the ratio of free cholesterol to total lipids in very large VLDL particles (OR: 1.399, 95% CI: 1.002-1.954, p = 0.048) and IL-16 (OR: 0.773, 95% CI: 0.608-0.983, p = 0.036). IL-16 was found to partially mediate the impact of circulating metabolites on PMOP, with a mediation effect of 10.4%. Conclusion: This study underscores the crucial role of circulating metabolites and inflammatory factors in PMOP pathogenesis. A causal relationship between circulating metabolites and PMOP was established, with IL-16 mediating some effects. These findings hold promise for clinical applications in early detection, personalized medicine, and the identification of therapeutic targets for PMOP.

Age Is a Key Factor Influencing the Choice of Treatment for Primary Patellar Dislocation: A Systematic Review and Meta-analysis.

Primary patellar dislocation has a certain recurrence rate after either conservative or surgical treatment, and the optimal treatment for patients with primary patellar dislocation of different ages remains unclear. This study aims to compare the clinical efficacy of surgical and conservative treatments for primary patellar dislocation across different age groups. According to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist, we conducted a systematic search for randomized controlled trials. We searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases for randomized controlled trials of primary patellar dislocation treated surgically or conservatively up to January 2023. Data searching, extraction, analysis, and quality assessment were carried out in accordance with the Cochrane Collaboration guidelines. A total of nine studies with 433 patients were included in our study. There was no statistically significant difference between the two treatment modalities in terms of Kujala score, pain score, patient satisfaction, reoperation, and Tegner score. The rate of re-dislocation after surgical treatment is lower than that after conservative treatment. Subgroup analysis based on mean age showed that when the age was >20 years, Kujala scores were higher after surgical treatment than after conservative treatment (p < 0.0001, 95% confidence interval [CI] = 10.41-21.30). When the age was ≤20 years, the difference in Kujala scores between the two treatment modalities was not statistically significant. When the age was >20 years, the recurrence rate of patellar dislocation was lower after surgical treatment than after conservative treatment (p = 0.009, 95% CI = 0.08-0.70). When the age was ≤20 years, the difference in the recurrence rate of patellar dislocation between the two treatment modalities was not statistically significant. When the age of patients with primary patellar dislocation is ≤20 years, both surgical and conservative treatments result in similar clinical outcomes. When the age is >20 years, better clinical outcomes can be achieved by opting for surgical treatment. Therefore, surgery may be a better option for patients with primary patellar dislocation whose age is >20 years.

PGRMC2 influences the onset of postmenopausal osteoporosis through disulfidptosis in monocytes: Evidence from experimental validation and Mendelian randomization.

This study explores the role of disulfidptosis in monocytes and its relation to postmenopausal osteoporosis (PMOP). Using single-cell RNA sequencing and microarray assays, we identified key genes: LONRF1, ACAP2, IPO9, and PGRMC2. Through differential analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and machine learning, these genes were linked to PMOP. Functional enrichment and ROC curve analysis demonstrated their effectiveness in distinguishing postmenopausal fracture patients from healthy individuals. Notably, PGRMC2 exhibited significant expression differences, highlighted by a notable Area Under the Curve (AUC) value of 0.665. Further investigation involved Western blotting and immunohistochemical assays, revealing decreased PGRMC2 expression in ovariectomized (OVX) mice. This decrease was consistent across both experimental methods, emphasizing PGRMC2's role in PMOP. Moreover, PGRMC2 was predominantly present in macrophages compared to monocytes within bone tissue and was significantly located in bone marrow mesenchymal stem cells (BM-MSCs) in PMOP patients. It was also abundantly found in osteoblasts and adipocytes. Additionally, a Mendelian randomization analysis using the TwoSampleMR R package, with data from decode and GWAS databases, was conducted. This analysis showed a significant impact of PGRMC2 on osteoporosis risk (p = 0.0048, OR = 0.6836), suggesting a potential protective effect against the disease. Our results suggest that PGRMC2 may facilitate the differentiation of monocytes into macrophages in bone tissue, influencing the behavior of BM-MSCs. This, in turn, could impact the progression and severity of PMOP. The study provides new insights into the molecular mechanisms underlying postmenopausal osteoporosis and highlights the potential of PGRMC2 as a therapeutic target or biomarker for this condition.

Unraveling Key m6A Modification Regulators Signatures in Postmenopausal Osteoporosis through Bioinformatics and Experimental Verification.

OBJECTIVE: Bone marrow mesenchymal stem cells (BMSCs) show significant potential for osteogenic differentiation. However, the underlying mechanisms of osteogenic capability in osteoporosis-derived BMSCs (OP-BMSCs) remain unclear. This study aims to explore the impact of YTHDF3 (YTH N6-methyladenosine RNA binding protein 3) on the osteogenic traits of OP-BMSCs and identify potential therapeutic targets to boost their bone formation ability. METHODS: We examined microarray datasets (GSE35956 and GSE35958) from the Gene Expression Omnibus (GEO) to identify potential m6A regulators in osteoporosis (OP). Employing differential, protein interaction, and machine learning analyses, we pinpointed critical hub genes linked to OP. We further probed the relationship between these genes and OP using single-cell analysis, immune infiltration assessment, and Mendelian randomization. Our in vivo and in vitro experiments validated the expression and functionality of the key hub gene. RESULTS: Differential analysis revealed seven key hub genes related to OP, with YTHDF3 as a central player, supported by protein interaction analysis and machine learning methodologies. Subsequent single-cell, immune infiltration, and Mendelian randomization studies consistently validated YTHDF3's significant link to osteoporosis. YTHDF3 levels are significantly reduced in femoral head tissue from postmenopausal osteoporosis (PMOP) patients and femoral bone tissue from PMOP mice. Additionally, silencing YTHDF3 in OP-BMSCs substantially impedes their proliferation and differentiation. CONCLUSION: YTHDF3 may be implicated in the pathogenesis of OP by regulating the proliferation and osteogenic differentiation of OP-BMSCs.

METTL3-mediated m6A modification increases Hspa1a stability to inhibit osteoblast aging.

Senile osteoporosis is mainly caused by osteoblasts attenuation, which results in reduced bone mass and disrupted bone remodeling. Numerous studies have focused on the regulatory role of m6A modification in osteoporosis; however, most of the studies have investigated the differentiation of bone marrow mesenchymal stem cells (BMSCs), while the direct regulatory mechanism of m6A on osteoblasts remains unknown. This study revealed that the progression of senile osteoporosis is closely related to the downregulation of m6A modification and methyltransferase-like 3 (METTL3). Overexpression of METTL3 inhibits osteoblast aging. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that METTL3 upregulates the stability of Hspa1a mRNA, thereby inhibiting osteoblast aging. Moreover, the results demonstrated that METTL3 enhances the stability of Hspa1a mRNA via m6A modification to regulate osteoblast aging. Notably, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) participates in stabilizing Hspa1a mRNA in the METTL3-mediated m6A modification process, rather than the well-known degradation function. Mechanistically, METTL3 increases the stability of Hspa1a mRNA in a YTHDF2-dependent manner to inhibit osteoblast aging. Our results confirmed the significant role of METTL3 in osteoblast aging and suggested that METTL3 could be a potential therapeutic target for senile osteoporosis.

Efficacy and safety of odanacatib for osteoporosis treatment: a systematic review and meta-analysis.

PURPOSE: Osteoporosis is a metabolic bone disease that commonly results in middle-aged and elderly people following fractures. Odanacatib (ODN), a potential osteoporosis medication, was stopped in the Long-term Odanacatib Fracture Trial (LOFT) phase III study because it increased the risk of stroke. Herein, we conducted a systematic review and meta-analysis to further assess the efficacy and safety of ODN in osteoporosis treatment. METHODS: We searched the PubMed, EMBASE, Cochrane Library, and Web of Science, using the core search terms "osteoporosis" and "odanacatib." The primary outcomes were the percentage change in markers of bone turnover and bone formation as well as that in the bone mineral density (BMD) of the lumbar spine, hip, femoral neck, and greater trochanter. The secondary outcome was the risk of adverse events (AEs), used to explore the safety of ODN. RESULTS: Ten articles-all double-blinded, randomized, placebo-controlled trials-were included. All trials were considered to be of high quality if they met the inclusion and exclusion criteria. We found that ODN increases BMD in the lumbar spine, total hip, and femoral neck, whereas it decreases the concentration of serum C-telopeptides of type I collagen (sCTx) and urinary N-telopeptide/creatinine ratio (uNTx/Cr). We found no significant differences in total, drug-related, serious, or skin AEs between the ODN and control groups. However, significant differences in fracture and stroke AEs were found between the ODN and control groups. CONCLUSION: ODN is an appealing long-term osteoporosis treatment method; however, further research should focus on the potential increased risk of fracture and stroke.

Strategies for promoting tendon-bone healing: Current status and prospects.

Tendon-bone insertion (TBI) injuries are common, primarily involving the rotator cuff (RC) and anterior cruciate ligament (ACL). At present, repair surgery and reconstructive surgery are the main treatments, and the main factor determining the curative effect of surgery is postoperative tendon-bone healing, which requires the stable combination of the transplanted tendon and the bone tunnel to ensure the stability of the joint. Fibrocartilage and bone formation are the main physiological processes in the bone marrow tract. Therefore, therapeutic measures conducive to these processes are likely to be applied clinically to promote tendon-bone healing. In recent years, biomaterials and compounds, stem cells, cell factors, platelet-rich plasma, exosomes, physical therapy, and other technologies have been widely used in the study of promoting tendon-bone healing. This review provides a comprehensive summary of strategies used to promote tendon-bone healing and analyses relevant preclinical and clinical studies. The potential application value of these strategies in promoting tendon-bone healing was also discussed.

Identification of key gene contributing to vitiligo by immune infiltration.

BACKGROUND: A deeper understanding of new prognostic and diagnostic biomarkers for vitiligo, an autoimmune disease, is needed. The purpose of this study is to identify the underlying long noncoding RNAs (lncRNAs) and immune infiltration related to the cause of vitiligo. METHODS: The microarray data (GSE75819) were available to be downloaded from NCBI-GEO. Eight hub genes were identified from the Protein-protein interaction (PPI) network by the dissection of differentially expressed genes (DEG), Kyoto Gene and Genomic Encyclopedia (KEGG) expansion pathway, and Gene Ontology (GO). Further analysis based on the immune infiltration as well as the correlation between DEGs and immune cells was performed. Our conclusions were verified by using the GSE534 eventually. RESULTS: According to our analysis, we obtained a total of 666 DEGs and 8 hub genes that include ECT2, CCT8, VRK1, UQCRH, EBNA1BP2, CRY2, IFIH1, and BCCIP, which may play an important role in vitiligo. Moreover, the immune infiltration profiles varied significantly between normal and vitiligo tissues. Compared with normal tissues, vitiligo tissues contained a greater proportion of mast cells (P<0.05). The analysis revealed that T cells regulatory (Tregs) have a negative correlation with the VRK1 expression (R=-0:77, P<0.001), whereas the mast cells resting have a positive correlation with the VRK1 expression (R=0:72, P<0.001) in vitiligo. CONCLUSION: The gene expression profile of vitiligo was realized by a bioinformatics method. The expressions of 8 hub genes and 22 immune cells were found, as the same as CRY2 and VRK1 have a special correlation with immune cells, which may be a significant cause of the pathogenesis of vitiligo. This provides a new idea for the diagnosis and treatment of vitiligo.

Hesperidin Ameliorates Dexamethasone-Induced Osteoporosis by Inhibiting p53.

Osteoporosis is one of the most frequent skeletal disorders and a major cause of morbidity and mortality in the expanding aging population. Evidence suggests that hesperidin may have a therapeutic impact on osteoporosis. Nevertheless, little is known about the role of hesperidin in the development of osteoporosis. Bioinformatics analyses were carried out to explore the functions and possible molecular mechanisms by which hesperidin regulates osteogenic differentiation. In the present study, we screened and harvested 12 KEGG pathways that were shared by hesperidin-targeted genes and osteoporosis. The p53 signaling pathway was considered to be a key mechanism. Our in vitro results showed that hesperidin partially reversed dexamethasone-induced inhibition of osteogenic differentiation by suppressing the activation of p53, and suggest that hesperidin may be a promising candidate for the treatment against dexamethasone-induced osteoporosis.

Silver nanoparticles induce cell death of colon cancer cells through impairing cytoskeleton and membrane nanostructure.

Globally, colon cancer is a predominant cause of increased morbidity and mortality annually; therefore, in addition to traditional treatments, new protocols are under continuous investigation. Nanotechnology-based cancer therapy is a new strategy and considered one of the most promising research directions for colon cancer. In this study, we used a silver nanoparticle (AgNP)-based methodology to treat colon cancer cells, and single cell approaches to examine how AgNPs exerted inhibiting effects on cells. We found that AgNPs could apparently destroy cytoskeleton and topography structures, alter cell membrane nanostructures, and thus increase membrane roughness, and depress cell membrane adhesion properties and cell stiffness. We also found that AgNPs caused mitochondrial dysfunctions including hyperpolarization of membrane potential and reactive oxygen species (ROS) accumulation. Notably, AgNPs altered all phenotypes or functions of cells in a dose-dependent manner. Therefore, our research provided a new paradigm for revealing killing mechanisms of AgNPs against colon cancer cells from single cell biophysical aspects, which could advance AgNP-based nanotechnology cancer therapy.

MC8 peptide-mediated Her-2 receptor targeting based on PEI-ß-CyD as gene delivery vector.

A novel vector with high gene delivery efficiency and special cell targeting ability was developed using a good strategy that utilized low molecular weight polyethylenimine (PEI; molecular weight, 600 KDa [PEI600]) cross-linked to ß-cyclodextrin (ß-CyD) via a facile synthetic route. Human epidermal growth factor receptor 2 (Her-2) are highly expressed in a variety of human cancer cells and are potential targets for cancer therapy. MC8 peptides, which have been proven to combine especially with Her-2 on cell membranes were coupled to PEI-ß-CyD using N-succinimidyl-3-(2-pyridyldithio) propionate as a linker. The ratios of PEI600, ß-CyD, and peptide were calculated based on proton integral values obtained from the (1)H-NMR spectra of the resulting products. Electron microscope observations showed that MC8-PEI-ß-CyD can efficiently condense plasmid DNA (pDNA) into nanoparticles of about 200 nm, and MTT assays suggested the decreased toxicity of the polymer. Experiments on gene delivery efficiency in vitro showed that MC8-PEI-ß-CyD/pDNA polyplexes had significantly greater transgene activities than PEI-ß-CyD/pDNA in the Skov3 and A549 cells, which positively expressed Her-2, whereas, no such effect was observed in the MCF-7 cells, which negatively expressed Her-2. Our current research indicated that the synthesized nonviral vector shows improved gene delivery efficiency and targeting specificity in Her-2 positive cells.