Integrity of the ECM Influences the Bone Regenerative Property of ECM/Dicalcium Phosphate Composite Scaffolds.

Due to the limitation of clinical autologous bone supply and other issues, the development of bone regeneration materials is still a hot topic. Natural tissue-derived bone repair materials have good biocompatibility and degradability, but their structure and properties are likely to be adversely affected during terminal sterilization. In this study, a composite scaffold consisting of the acellular extracellular matrix and dicalcium phosphate (ECM/DCP) was fabricated and terminally sterilized by γ-ray irradiation. In addition, the ECM/DCP scaffold was saturated with water and was also sterilized by γ-ray irradiation (RX-ECM/DCP). Results showed that the triple helix structure of collagen was better maintained in RX-ECM/DCP than in ECM/DCP. The thermal stability of RX-DCP/ECM was much better than that of ECP/ECM. The in vitro and in vivo performances of both types of scaffolds were also evaluated. The RX-ECM/DCP scaffold exhibited better in vitro bioactivity than that of the ECM/DCP scaffold as evidenced by more mineral formation in the simulated body fluid. In addition, RX-ECM/DCP also induced more effective bone regeneration than the ECM/DCP scaffold did in a rat calvarial defect model. Results sufficiently demonstrated that the addition of water to the scaffold could protect the structure of the ECM/DCP scaffold from being damaged by γ-ray irradiation during the terminal sterilization process. In summary, this study demonstrated a means to protect the ECM structure, which in turn led to the improvement of bone regenerative properties of the materials during γ-ray irradiation of ECM-based bone repair materials.

Relationship Between Serum Amino Acid Levels and Bone Mineral Density: A Mendelian Randomization Study.

Background: This study aimed to explore the association between serum amino acids (AAs) levels and bone mineral density (BMD). Methods: We performed a two-sample Mendelian randomization (MR) analysis to analyze the associations between the levels of eight AAs and BMD values by using summary-level genome-wide association study (GWAS) data. We applied the MR Steiger filtering method and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test to check for and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. The associations were estimated with the inverse variance weighted (IVW), MR-Egger, weighted median and MR Robust Adjusted Profile Score (MR.RAPS) methods. Results: Our study found that genetically increased isoleucine (Ile) [IVW: effect = 0.1601, 95% confidence interval (CI) = 0.0604 ~ 0.2597, p = 0.0016] and valine (Val) levels (IVW: effect = 0.0953, 95% CI = 0.0251 ~ 0.1655, p = 0.0078) were positively associated with total body BMD (TB-BMD). The results also revealed that genetically increased tyrosine (Tyr) levels were negatively associated with TB-BMD (IVW: effect = -0.1091, 95% CI = -0.1863 ~ -0.0320, p = 0.0055). Conclusions: In this study, associations between serum AA levels and BMD were established. These findings underscore the important role that serum AAs play in the development of osteoporosis and provide evidence that osteoporosis can be prevented and treated by the intake of certain AAs.

Bidirectional Causal Associations Between Inflammatory Bowel Disease and Ankylosing Spondylitis: A Two-Sample Mendelian Randomization Analysis.

BACKGROUND: Associations between inflammatory bowel disease (IBD) [including ulcerative colitis (UC) and Crohn's disease (CD)] and ankylosing spondylitis (AS) were discovered in observational studies, but no evidence supported the causal relationship between the two diseases. METHODS: We employed two-sample Mendelian randomization (MR) to estimate the unconfounded bidirectional causal associations between IBD (including UC and CD) and AS. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) after strictly assessing the quality of the studies in the IEU GWAS database. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results. RESULTS: We found positive causal effects of genetically increased UC, CD, and IBD risk on AS (e.g., UC and AS, IVW OR: 1.0256, 95% CI: 1.0130∼1.0385, p = 6.43E-05). However, we did not find significant causal associations of AS with UC, CD, or IBD (e.g., AS and UC, IVW OR: 1.1858, 95% CI: 0.8639∼1.6278, p = 0.2916). The sensitivity analysis also confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., UC and AS, MR-Egger: intercept p = 0.1326). The leave-one-out analysis also demonstrated that the observed links were not driven by SNP. No evidence of heterogeneity was found between the genetic variants (e.g., UC and AS, MR-Egger: Q statistic = 43.1297, I 2<0.0001, p = 0.7434). CONCLUSION: Our results provide new evidence indicating there are positive causal effects of IBD on AS in the European population. We suggest that the features of inflammatory bowel disease in particular should be assessed in the diagnosis of ankylosing spondylitis. We also provide some advice for preventing and treating the two diseases.

Type 2 Diabetes and Glycemic Traits Are Not Causal Factors of Osteoarthritis: A Two-Sample Mendelian Randomization Analysis.

BACKGROUND: It remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA). METHODS: Here, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single-nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG), and 2-h postprandial glucose (2hGlu) from genome-wide association studies (GWAS). We used the MR inverse variance weighted (IVW), the MR-Egger method, the weighted median (WM), and the Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG, and 2hGlu with hip and knee OA risks. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results. RESULTS: We did not find statistically significant causal effects of genetically increased T2D risk, FG, and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR-Egger OR = 1.1708, 95% CI 0.9469-1.4476, p = 0.1547). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR-Egger, intercept = -0.0105, p = 0.1367). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR-Egger Q = 30.1362, I 2 < 0.0001, p = 0.6104). CONCLUSION: Our MR study did not support causal effects of a genetically increased T2D risk, FG, and 2hGlu on hip and knee OA risk.

Tangduqing Granules Attenuate Insulin Resistance and Abnormal Lipid Metabolism through the Coordinated Regulation of PPARγ and DGAT2 in Type 2 Diabetic Rats.

Insulin resistance (IR) is a vital hallmark of type 2 diabetes mellitus, which is characterized by an impaired ability of insulin to promote glucose uptake and utilization. Lipid deposition is closely associated with impaired insulin sensitivity. PPARγ plays an important role in glucose homeostasis, adipocyte differentiation, and insulin sensitivity. Likewise, DGAT2 also exerts a crucial role in integrating carbohydrate and lipid metabolism in the liver. The present study is aimed at evaluating a Chinese medicinal formula, Tangduqing granules (TDQ), with multifaceted actions against lipid and glucose metabolism disorder and IR of type 2 diabetes. An animal model of type 2 diabetes was developed by high-fat diet feeding plus low-dose streptozotocin injection. After oral administration of TDQ for 5 weeks, the effects on glucose and lipid metabolism and the underlying mechanism were evaluated by biochemical, histological, RT-PCR, and western blotting methods. The results showed that TDQ decreased fasting blood glucose, ameliorated glucose tolerance, and improved IR. Besides, TDQ regulated hyperlipidemia symptoms, decreased serum lipid levels and liver TG, and reduced hepatic steatosis in a type 2 diabetic rat model. Furthermore, TDQ reversed diabetes-induced decrease in the mRNA and protein expression of PPARγ and elevation in the mRNA and protein levels of DGAT2 in the liver. In addition, we showed that interference of TDQ ameliorated palmitate-induced glucose and lipid metabolic abnormalities in HepG2 cells. TDQ are, therefore, a potential Chinese medicinal formula that relieves IR and lipid metabolism disorder might be through promotion of PPARγ and decrease of DGAT2 expression.