Associations of postoperative outcomes with geriatric nutritional risk index after conventional and robotic-assisted total knee arthroplasty: a randomized controlled trial.

BACKGROUND: The association between postoperative outcomes of robotic-assisted total knee arthroplasty (RA-TKA) and nutrition status among elderly adults remained unclear. The authors aimed to evaluate these associations and provide a nutrition status reference for the surgical technique selection of TKA. METHODS: In the present study, the authors used data from a multicenter, prospective, randomized controlled project, which recruited patients underwent TKA therapy. A total of 88 elderly adults (age ≥65 years old) were included in this study. Their preoperative and postoperative demographic data and radiographic parameters were collected. Clinical outcomes, including postoperative hip-knee-ankle (HKA) angle deviation, knee society score (KSS), 10 cm visual analog scale, and so on, were observed and compared between the RA-TKA group and the conventional TKA group. Logistic regression was performed to adjust several covariates. In addition, according to the results of restricted cubic splines analyses, all participants were categorized into two groups with GNRI≤100 and GNRI >100 for further subgroup analyses. RESULTS: Our results showed despite having a lower postoperative HKA angle deviation, the RA-TKA group had a similar postoperative KSS score compared with the conventional TKA group in elderly adults. Among elderly patients with GNRI>100, RA-TKA group achieved significantly more accurate alignment (HKA deviation, P =0.039), but did not obtain more advanced postoperative KSS scores because of the compensatory effect of good nutrition status. However, among elderly patients with GNRI≤100, RA-TKA group had significantly higher postoperative KSS scores compared to the conventional TKA group ( P =0.025) and this association were not altered after adjustment for other covariates. CONCLUSION: Considering the clinical outcomes of conventional TKA may be more susceptible to the impact of nutrition status, elderly patients with GNRI≤100 seem to be an applicable population for RA-TKA, which is more stable and would gain significantly more clinical benefits compared with conventional TKA.

Enhanced Osteolysis Targeted Therapy through Fusion of Exosomes Derived from M2 Macrophages and Bone Marrow Mesenchymal Stem Cells: Modulating Macrophage Polarization.

Aseptic loosening of prostheses is a highly researched topic, and wear particle-induced macrophage polarization is a significant cause of peri-prosthetic osteolysis. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs-Exos) promote M2 polarization and inhibit M1 polarization of macrophages. However, clinical application problems such as easy clearance and lack of targeting exist. Exosomes derived from M2 macrophages (M2-Exos) have good biocompatibility, immune escape ability, and natural inflammatory targeting ability. M2-Exos and BMSCs-Exos fused exosomes (M2-BMSCs-Exos) are constructed, which targeted the osteolysis site and exerted the therapeutic effect of both exosomes. M2-BMSCs-Exos achieved targeted osteolysis after intravenous administration inhibiting M1 polarization and promoting M2 polarization to a greater extent at the targeted site, ultimately playing a key role in the prevention and treatment of aseptic loosening of prostheses. In conclusion, M2-BMSCs-Exos can be used as a precise and reliable molecular drug for peri-prosthetic osteolysis. Fused exosomes M2-BMSCs-Exos  were originally proposed and successfully prepared, and exosome fusion technology provides a new theoretical basis and solution for the clinical application of therapeutic exosomes.

Melatonin promotes the restoration of bone defects via enhancement of miR-335-5p combined with inhibition of TNFα/NF-κB signaling.

Accelerating the repair of a bone defect is crucial clinically due to the increased prevalence of trauma, tumor, and infections in bone. Studies have found that excess acute and chronic inflammation attenuate osteogenic differentiation of BMSCs (bone marrow mesenchymal stem cells). Moreover, TNF-α and NF-κB could inhibit osteoblasts differentiation of BMSCs and promote osteoclastogenesis via multiple mechanisms, such as increasing osteoclast precursor cells and acting synergistically with cell cytokines. However, melatonin could inhibit the expression of TNFα/NF-κB and promote bone formation by activating the Wnt/ß-catenin signaling pathway. However, there has been no evidence regarding the effect of melatonin on TNFα/NF-κB-inhibited osteoblastogenesis and bone formation. This study aimed to investigate the role of melatonin on TNFα/NF-κB-inhibited osteoblastogenesis and bone formation. Micro-CT, high-throughput screening, overexpression, and other methods were used, and we found that the number of osteoblasts was elevated with melatonin treatment. Additionally, TNFα/NF-κB signaling was inhibited, while miR-335-5p expression increased markedly following treatment with melatonin. Furthermore, miR-335-5p negatively regulated TNFα/NF-κB signaling, while miR-335-5p inhibitor ameliorated the effects of melatonin on TNFα/NF-κB. In conclusion, melatonin facilitates osteogenesis in bone defect healing by enhancing miR-335-5p expression and inhibiting the TNFα/NF-κB pathway.

Osteogenesis-Related Long Noncoding RNA GAS5 as a Novel Biomarker for Osteonecrosis of Femoral Head.

Background: The lack of effective biomarkers makes it difficult to achieve early diagnosis and intervention for osteonecrosis of the femoral head (ONFH). Hence, we aimed to identify novel long noncoding RNA (lncRNA) biomarkers for ONFH. Methods: High-throughput RNA sequencing was performed to detect lncRNA and mRNA expression levels in subchondral bone samples from three patients with ONFH and three patients with femoral neck fractures. Integrated bioinformatics analyses were conducted to identify lncRNAs associated with ONFH development and their potential functions and signaling pathways. A co-expression network was constructed based on the gene time-series expression data in GSE113253. After selecting lncRNA GAS5 as a novel biomarker for ONFH, bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation assays were performed to verify the association between lncRNA GAS5 and osteogenic differentiation. Alkaline phosphatase (ALP) staining and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to measure the osteogenic phenotype and lncRNA GAS5 expression. Finally, for further validation, ONFH rat models were established, and lncRNA GAS5 expression in subchondral bone was detected by RT-qPCR. Results: We identified 126 and 959 differentially expressed lncRNAs and genes, respectively. lncRNA GAS5 expression level was significantly downregulated in patients with ONFH compared to the control group patients. The BMSC osteogenic differentiation assays showed that ALP activity increased gradually from days 3 to 7, while the lncRNA GAS5 expression level was significantly upregulated in the osteogenic differentiation induction groups. Furthermore, in vivo experiments suggested that the bone volume/tissue volume value and trabecular thickness significantly decreased in the ONFH rat model group compared to the control group, whereas the trabecular space significantly increased in the ONFH group compared to the control group. In addition, the lncRNA GAS5 expression level significantly decreased in the ONFH rat model group. Conclusion: The lncRNA GAS5 expression level was highly associated with BMSC osteogenic differentiation and was significantly downregulated in both the subchondral trabecular bone tissue of ONFH patients and ONFH rat models. Therefore, lncRNA GAS5 can serve as an ONFH osteogenic biomarker to provide an effective target for early diagnosis and molecular therapy of ONFH.

Melatonin increases bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats via the promotion of osteogenesis.

BACKGROUND: Osteoporosis is a disease threatening the health of millions of individuals. Melatonin is found to be a potential anti-osteoporosis drug. However, whether melatonin plays a role against osteoporosis at different stages of the menopause and the underlying mechanisms are unknown. METHODS: Ovariectomy was utilized as a model of perimenopausal and postmenopausal osteoporosis. A total of 100 mg/kg melatonin, or solvent alone, was added to the drinking water of the rats over 8 weeks. Perimenopausal rats immediately received intervention following ovariectomy while postmenopausal rats received intervention 8 weeks after ovariectomy. All rats underwent overdose anesthesia following intervention after which blood samples and femurs were collected for further analysis. Rat femurs were scanned using micro-CT and examined histologically. The serum levels of melatonin and osteogenic biochemical markers were measured and the expression of osteogenesis-associated genes (Runx2, Sp7) were quantified by real-time quantitative PCR. Alkaline phosphatase (ALP) activity and the gene expression (Col1a1, Runx2, Alpl, and Bglap) were measured after bone marrow mesenchymal stem cells (BMSCs) were osteogenically induced, both with and without melatonin in vitro. ALP staining and Alizarin Red S staining were used to identify osteogenesis. RESULTS: Analysis by micro-CT and histological staining demonstrated that bone mass decreased and bone microarchitecture deteriorated over time after ovariectomy. Intervention with melatonin increased bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats. Serum levels of ALP continuously increased after ovariectomy while osteocalcin levels initially rose, then decreased. Melatonin increased the serum levels of ALP and osteocalcin and mRNA expression levels of Runx2 and Sp7 in normal and postmenopausal rats, the opposite of the markers in perimenopausal rats. In vitro study demonstrated that 100 µmol/L melatonin increased the mRNA expression of Col1a1, Runx2, and Alpl three and/or seven days after intervention, and Alpl and Bglap 14 d after intervention. Melatonin increased ALP activity and the extent of ALP and matrix mineralization in the late stage of osteogenesis. CONCLUSIONS: Bone mass continuously decreased after ovariectomy, while melatonin increased bone mass and ameliorated bone metabolism in normal, perimenopausal, and postmenopausal osteoporotic rats due to the induction of osteogenic differentiation in BMSCs.

Screening of differentially expressed miRNAs during osteogenic/odontogenic differentiation of human dental pulp stem cells exposed to mechanical stress.

MicroRNAs (miRNAs) have been demonstrated as crucial transcriptional regulators in proliferation, differentiation, and tumorigenesis. The comprehensive miRNA profiles of osteogenic/odontogenic differentiation of human dental pulp stem cells (hDPSCs) under the condition of mechanical stress remains largely unknown. In this study, we aimed to discover the miRNA expression profiles of hDPSCs exposed to mechanical stress under the osteogenic/odontogenic process. We found that mechanical stress (0.09 MPa and 0.18 MPa, respectively, 30 min/day) significantly promoted the proliferation of hDPSCs since the fifth day. The expressions of DSPP, DMP1, and RUNX2 were significantly increased on day 7 in the presence of 0.09 MPa and 0.18 MPa mechanical stress. On day 14, the expression levels of DSPP, DMP1, and RUNX2 were decreased in the presence of mechanical stress. Among 2578 expressed miRNAs, 5 miRNAs were upregulated and 3 miRNAs were downregulated. Six hub target genes were merged in protein-protein interactions (PPI) network analysis, in which existed only one sub-network. Bioinformatics analysis identified an array of affected signaling pathways involved in the development of epithelial and endothelial cells, cell-cell junction assembly, Rap1 signaling pathway, regulation of actin cytoskeleton, and MAPK signaling pathway. Our results revealed the miRNA expression profiles of osteogenic/odontogenic differentiation of hDPSCs under mechanical stress and identified eight miRNAs that were differentially expressed in response to the mechanical stress. Bioinformatics analysis also showed that various signaling pathways were affected by mechanical stress.

Establishment of a novel nomogram for the clinically diagnostic prediction of minimal change disease, -a common cause of nephrotic syndrome.

BACKGROUND: Minimal change disease (MCD) is one of the major causes of nephrotic syndrome (NS). A confirmed MCD diagnosis mainly depends on renal biopsy at present, which is an invasive procedure with many potential risks. The overall incidence of complications caused by renal biopsy procedures has been reported as approximately 11 and 6.6% outside and within China, respectively. Unfortunately, there is currently no noninvasive procedure or practical classification method for distinguishing MCD from other primary glomerular diseases available. METHOD: A total of 1009 adult patients who underwent renal biopsy between January 2017 and November 2019 were enrolled in this study. Twenty-five parameters extracted from patient demographics, clinical manifestations, and laboratory test results were statistically analysed. LASSO regression analysis was further performed on these parameters. The parameters with the highest area under the curve (AUC) were selected and used to establish a logistic diagnostic prediction model. RESULTS: Of the 25 parameters, 14 parameters were significantly different (P < 0.05). MCD patients were mostly younger (36 (22, 55) vs. 41 (28.75, 53)) and male (59% vs. 52%) and had lower levels of diastolic blood pressure (DBP) (79 (71, 85.5) vs. 80 (74, 89)) and IgG (5.42 (3.17, 6.36) vs. 9.38 (6.79, 12.02)) and higher levels of IgM (1.44 (0.96, 1.88) vs. 1.03 (0.71, 1.45)) and IgE (160 (46.7, 982) vs. 47.3 (19, 126)) than those in the non-MCD group. Using the LASSO model, we established a classifier for adults based on four parameters: DBP and the serum levels of IgG, IgM, IgE. We were able to clinically classify adult patients with NS into MCD and non-MCD using this model. The validation accuracy of the logistic regression model was 0.88. A nomogram based on these four classifiers was developed for clinical use that could predict the probability of MCD in adult patients with NS. CONCLUSIONS: A LASSO model can be used to distinguish MCD from other primary glomerular diseases in adult patients with NS. Combining the model and the nomogram potentially provides a novel and valuable approach for nephrologists to diagnose MCD, avoiding the complications caused by renal biopsy.

Plastin 1 drives metastasis of colorectal cancer through the IQGAP1/Rac1/ERK pathway.

Tumor metastasis is the dominant cause of death in colorectal cancer (CRC) patients, and it often involves dysregulation of various cytoskeletal proteins. Plastin 1 (PLS1) is an actin-bundling protein that has been implicated in the structure of intestinal epithelial microvilli; however, its role in CRC metastasis has not yet been determined. In this study, we demonstrated that PLS1 is highly expressed in 33.3% (45/135) of CRC patients and is correlated with lymph node metastasis and poor survival. In in vitro and in vivo experiments, PLS1 induced the migration and invasion of CRC cells and the metastases to the liver and lung in mice. Moreover, the expressions of key factors for CRC metastases, matrix metalloproteinase (MMP) 9 and 2, were enhanced by PLS1, which was dependent on phosphorylating ERK1/2 activated by IQGAP1/Rac1 signaling. The connection between these signals and PLS1 was further confirmed in CRC tissues of patients and the metastatic nodules from a mouse model. These findings suggest that PLS1 promotes CRC metastasis through the IQGAP1/Rac1/ERK pathway. Targeting PLS1 may provide a potential approach to inhibit the metastasis of CRC cells.

Bone marrow macrophage M2 polarization and adipose-derived stem cells osteogenic differentiation synergistically promote rehabilitation of bone damage.

By differentiating into and the balance being regulated between M1 (pro-inflammatory) and M2 (anti-inflammatory) heterogeneous populations, macrophages play critical roles during the host immune response in various physiological contexts in both health and diseases. Besides regulating innate and adaptive immune capacity, macrophages are also decisively involved in tissue homeostasis. However, how resident macrophages are regulated after tissue damages is still far from elucidation. In the present study, we found that adipose-derived stem cells (ADSCs) apparently promote bone defect rehabilitation in vivo via skewing differentiation of bone marrow-derived macrophage (BMDMs) towards anti-inflammatory M2 macrophages. In vitro data demonstrated that although ADSCs have the potential to differentiate to osteoblasts and adipose cells by using standard tissue culture-differentiating conditions, these mesenchymal progenitors are mainly regulated to differentiate into osteoblasts with overexpressed runt-related transcription factor 2, osteoprotegerin, osterix, and downregulated receptor activator of nuclear factor κB ligand in the presence of BMDMs-conditioned medium. Whereas BMDMs are polarized toward M2 macrophages with higher levels of arginase 1 and mannose receptor, but lower levels of inducible nitric oxide synthase and tumor necrosis factor-α when cocultured with ADSCs. In short, all these findings collectively demonstrated that ADSCs and resident host cells can synergistically contribute to the bony repair through mutual regulation of their differentiation and cytokine secretion.