Causal Relationship between Gut Microbiota, Metabolites, and Sarcopenia: A Mendelian Randomization Study.

BACKGROUND: Gut microbiota imbalance and sarcopenia are frequently observed in the elderly population. Gut Microbiota and their metabolites are considered risk factors contributing to the heightened risk of sarcopenia, but whether these associations are causal remains unclear. METHODS: We conducted linkage disequilibrium score regression and two-sample Mendelian randomization methods with SNPs sourced from large-scale genome-wide association studies as instrumental variables to examine the causal associations linking gut microbiota with their metabolites to the sarcopenia. Following the MR analysis, subsequent sensitivity analyses were conducted to reinforce the robustness and credibility of the obtained results. RESULTS: MR analysis yielded compelling evidence demonstrating the correlation between genetically predicted gut microbiota and metabolites and the risk of sarcopenia. The abundance of Porphyromonadaceae, Rikenellaceae, Terrisporobacter, and Victivallis was found to be associated with WP. Our study also found suggestive associations of 12 intestinal bacteria with ALM, and of Streptococcaceae, Intestinibacter, Paraprevotella, Ruminococcaceae UCG009, and Sutterella with GS. Specifically, we identified 21 gut microbiota-derived metabolites that may be associated with the risk of sarcopenia. CONCLUSIONS: Utilizing a two-sample MR approach, our study elucidates the causal interplay among gut microbiota, gut microbiota-derived metabolites, and the occurrence of sarcopenia. These findings suggest that gut microbiota and metabolites may represent a potential underlying risk factor for sarcopenia, and offer the promise of novel therapeutic focal points.

Obesity induces osteoimmunology imbalance: Molecular mechanisms and clinical implications.

The notion that obesity can be a protective factor for bone health is a topic of ongoing debate. Increased body weight may have a positive impact on bone health due to its mechanical effects and the production of estrogen by adipose tissue. However, recent studies have found a higher risk of bone fracture and delayed bone healing in elderly obese patients, which may be attributed to the heightened risk of bone immune regulation disruption associated with obesity. The balanced functions of bone cells such as osteoclasts, osteoblasts, and osteocytes, would be subverted by aberrant and prolonged immune responses under obese conditions. This review aims to explore the intricate relationship between obesity and bone health from the perspective of osteoimmunology, elucidate the impact of disturbances in bone immune regulation on the functioning of bone cells, including osteoclasts, osteoblasts, and osteocytes, highlighting the deleterious effects of obesity on various diseases development such as rheumatoid arthritis (RA), osteoarthritis (AS), bone fracture, periodontitis. On the one hand, weight loss may achieve significant therapeutic effects on the aforementioned diseases. On the other hand, for patients who have difficulty in losing weight, the osteoimmunological therapies could potentially serve as a viable approach in halting the progression of these disease. Additional research in the field of osteoimmunology is necessary to ascertain the optimal equilibrium between body weight and bone health.

B vitamins and bone health: a meta-analysis with trial sequential analysis of randomized controlled trials.

Our study showed that B vitamins did not have significant effect on fracture incidence, bone mineral density, and bone turnover markers. However, the research data of B vitamins on bone mineral density and bone turnover markers are limited, and more clinical trials are needed to draw sufficient conclusions. PURPOSE: The objective of this study was to identify the efficacy of B vitamin (VB) (folate, B6, and B12) supplements on fracture incidence, bone mineral density (BMD), and bone turnover markers (BTMs). METHODS: A comprehensive search was performed in PubMed, MEDLINE, EMBASE, Cochrane databases, and ClinicalTrials.gov up to September 4, 2023. The risk of bias was assessed according to Cochrane Handbook and the quality of evidence was assessed according to the GRADE system. We used trial sequential analysis (TSA) to assess risk of random errors and Stata 14 to conduct sensitivity and publication bias analyses. RESULTS: Data from 14 RCTs with 34,700 patients were extracted and analyzed. The results showed that VBs did not significantly reduce the fracture incidence (RR, 1.06; 95% CI, 0.95 - 1.18; p = 0.33; I2 = 40%) and did not affect BMD in lumbar spine and femur neck. VBs had no significant effect on bone specific alkaline phase (a biomarker for bone formation), but could increase the serum carboxy-terminal peptide (a biomarker for bone resorption) (p = 0.009; I2 = 0%). The TSA showed the results of VBs on BMD and BTMs may not be enough to draw sufficient conclusions due to the small number of sample data included and needed to be demonstrated in more clinical trials. The inability of VBs to reduce fracture incidence has been verified by TSA as sufficient. Sensitivity analysis and publication bias assessment proved that our meta-analysis results were stable and reliable, with no significant publication bias. CONCLUSIONS: Available evidence from RCTs does not support VBs can effectively influence osteoporotic fracture risk, BMD, and BTMs. TRIAL REGISTRATION: PROSPERO registration number: CRD42023427508.

SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential therapeutic targets.

Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of the elderly population. Sirtuin 1 (SIRT1), as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in various aging-related signaling pathways and exert protective effect on many human diseases. SIRT1 functioned as an important role in the occurrence and progression of sarcopenia through regulating key pathways related to protein homeostasis, apoptosis, mitochondrial dysfunction, insulin resistance and autophagy in skeletal muscle, including SIRT1/Forkhead Box O (FoxO), AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor κB (NF-κB), SIRT1/p53, AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and SIRT1/live kinase B1 (LKB1)/AMPK pathways. However, the specific mechanisms of these processes have not been fully illuminated. Currently, several SIRT1-mediated interventions on sarcopenia have been preliminarily developed, such as SIRT1 activator polyphenolic compounds, exercising and calorie restriction. In this review, we summarized the predominant mechanisms of SIRT1 involved in sarcopenia and therapeutic modalities targeting the SIRT1 signaling pathways for the prevention and prognosis of sarcopenia.

Smoking and osteoimmunology: Understanding the interplay between bone metabolism and immune homeostasis.

Smoking continues to pose a global threat to morbidity and mortality in populations. The detrimental impact of smoking on health and disease includes bone destruction and immune disruption in various diseases. Osteoimmunology, which explores the communication between bone metabolism and immune homeostasis, aims to reveal the interaction between the osteoimmune systems in disease development. Smoking impairs the differentiation of mesenchymal stem cells and osteoblasts in bone formation while promoting osteoclast differentiation in bone resorption. Furthermore, smoking stimulates the Th17 response to increase inflammatory and osteoclastogenic cytokines that promote the receptor activator of NF-κB ligand (RANKL) signaling in osteoclasts, thus exacerbating bone destruction in periodontitis and rheumatoid arthritis. The pro-inflammatory role of smoking is also evident in delayed bone fracture healing and osteoarthritis development. The osteoimmunological therapies are promising in treating periodontitis and rheumatoid arthritis, but further research is still required to block the smoking-induced aggravation in these diseases. Translational potential: This review summarizes the adverse effect of smoking on mesenchymal stem cells, osteoblasts, and osteoclasts and elucidates the smoking-induced exacerbation of periodontitis, rheumatoid arthritis, bone fracture healing, and osteoarthritis from an osteoimmune perspective. We also propose the therapeutic potential of osteoimmunological therapies for bone destruction aggravated by smoking.

Global trends and research hotspots of reverse total shoulder arthroplasty: a bibliometric analysis from 1991 to 2022.

Reverse total shoulder arthroplasty (rTSA) has been demonstrated to be an effective intervention for various shoulder disorders. The number of rTSA-related studies performed has increased annually over the past three decades. The Journal of Shoulder and Elbow Surgery had the highest number of publications and citations in the rTSA-related research domain and is therefore considered to be the most influential journal in this field. The USA published the most publications and established a high degree of cooperation with many countries worldwide. The University of Florida, the Hospital for Special Surgery, and Rush University, Mayo Clinic were representative and active institutions in this field. It is anticipated that advancements in prosthesis design, specifically with regards to lateralized design concepts, expanding indications for rTSA, a trend toward younger patient populations, and the management of postoperative complications will emerge as research hotspots in the following years. The most valuable publications, influential journals, major researchers, and leading countries were analyzed. The findings of our study will help researchers gain insights into current research hotspots and frontiers and shape their research focus in the field of rTSA.

Accuracy and Consistency of 3-Dimensional Magnetic Resonance Imaging Is Comparable With 3-Dimensional Computed Tomography in Assessing Glenohumeral Instability: A Systematic Review.

PURPOSE: To compare the accuracy of 3-dimensional (3D) magnetic resonance imaging (MRI) with that of 3D computed tomography (CT) in evaluating glenoid bone loss (GBL). METHODS: This review aligned with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, the Cochrane Library, Embase, and Web of Science were obtained from data inception to August 28, 2023. The search term "glenoid bone loss" was extracted and analyzed via stringent inclusion and exclusion criteria. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 combined with the QUADAS-Comparative to assess the heterogeneity of included studies. RESULTS: A total of 1,589 related studies were retrieved, and 10 studies were finally included, of which a total of 143 shoulders were evaluated. The index test in QUADAS-Comparative was low risk in 9 studies. 3D MRI measurements of GBL were primarily best-fit circles (n = 9). In both clinical and cadaveric studies, the mean percentages of GBL measured by 3D MRI were 0.38% to 2.19% and 0.25% to 6.1% when compared with 3D CT and standard reference values, respectively. Intraclass correlation coefficient agreement greater than 0.9 between GBL percentages measured by 3D CT and 3D MRI. 3D MRI also could accurately measure glenoid width, glenoid height, humeral head width, and height. 3D MRI reconstruction time was similar to that of 3D CT, which was mainly 10 to 15 minutes. CONCLUSIONS: In both clinical and cadaveric studies, compared with 3D CT, 3D MRI is accurate and consistent in assessing glenohumeral bone, especially in measuring GBL, and the reconstruction time of 3D MRI is similar to 3D CT. LEVEL OF EVIDENCE: Level Ⅲ, systematic review of Level Ⅱ-Ⅲ studies.

Novel insights into the role of ubiquitination in osteoarthritis.

Ubiquitination (Ub) and deubiquitination are crucial post-translational modifications (PTMs) that precisely regulate protein degradation. Under the catalysis of a cascade of E1-E2-E3 ubiquitin enzymes, ubiquitination extensively regulates protein degradation exerting direct impact on various cellular processes, while deubiquitination opposes the effect of ubiquitination and prevents proteins from degradation. Notably, such dynamic modifications have been widely investigated to be implicated in cell cycle, transcriptional regulation, apoptosis and so on. Therefore, dysregulation of ubiquitination and deubiquitination could lead to certain diseases through abnormal protein accumulation and clearance. Increasing researches have revealed that the dysregulation of catalytic regulators of ubiquitination and deubiquitination triggers imbalance of cartilage homeostasis that promotes osteoarthritis (OA) progression. Hence, it is now believed that targeting on Ub enzymes and deubiquitinating enzymes (DUBs) would provide potential therapeutic pathways. In the following sections, we will summarize the biological role of Ub enzymes and DUBs in the development and progression of OA by focusing on the updating researches, with the aim of deepening our understanding of the underlying molecular mechanism of OA pathogenesis concerning ubiquitination and deubiquitination, so as to explore novel potential therapeutic targets of OA treatment.

Association between serum magnesium concentration and metabolic syndrome, diabetes, hypertension and hyperuricaemia in knee osteoarthritis: a cross-sectional study in Hunan Province, China.

OBJECTIVES: To examine the associations between serum magnesium (Mg) concentration with the prevalence of metabolic syndrome (MetS), diabetes mellitus (DM), hypertension (HP) and hyperuricaemia (HU) in patients with radiographic knee osteoarthritis (OA). METHODS: The present study was conducted at the Health Management Center of Xiangya Hospital. Radiographic OA was evaluated for patients aged over 40 years with basic characteristics and blood biochemical assessment. Serum Mg concentration was measured using the chemiluminescence method. MetS, DM, HP and HU were diagnosed based on standard protocols. The associations between serum Mg concentration with MetS, DM, HP and HU were evaluated by conducting multivariable adjusted logistic regression. RESULTS: A total of 962 patients with radiographic knee OA were included. Compared with the lowest quintile, the multivariable adjusted ORs and related 95% CIs of DM were 0.40 (95% CI 0.23 to 0.70, p=0.001), 0.33 (95% CI 0.18 to 0.60, p<0.001), 0.27 (95% CI 0.14 to 0.52, p<0.001) and 0.22 (95% CI 0.11 to 0.44, p<0.001) in the second, third, fourth and highest quintiles of serum Mg, respectively (p for trend <0.001); the multivariable adjusted ORs of HU were 0.33 (95% CI 0.19 to 0.59, p<0.001), 0.52 (95% CI 0.30 to 0.91, p=0.022) and 0.39 (95% CI 0.22 to 0.70, p=0.001) in the third, fourth and highest quintiles of serum Mg, respectively (p for trend <0.001); and the multivariable adjusted ORs of MetS were 0.59 (95% CI 0.36 to 0.94, p=0.027) in the second and 0.56 (95% CI 0.34 to 0.93, p=0.024) in the highest quintiles of serum Mg. However, the inverse association between serum Mg and the prevalence of MetS was non-linear (p for trend=0.067). There was no significant association between serum Mg and HP in patients with OA. CONCLUSIONS: The serum Mg concentration was inversely associated with the prevalence of MetS, DM and HU in patients with radiographic knee OA. LEVEL OF EVIDENCE: Level III, cross-sectional study.

Association Between Tibial Plateau Slopes and Anterior Cruciate Ligament Injury: A Meta-analysis.

PURPOSE: To investigate the associations of medial tibial plateau slope (MTPS), lateral tibial plateau slope (LTPS), and coronal tibial plateau slope (CTPS) with anterior cruciate ligament (ACL) injury both in the general population and in different gender subgroups. METHODS: PubMed, Ovid, Embase, and Scopus databases were searched through from inception to August 31, 2016. Observational studies reporting associations of MTPS/LTPS/CTPS with ACL injury were retrieved for analysis. Either a fixed- or random-effects model was used to calculate the overall standardized mean difference (SMD). Reviews, meeting abstracts, cadaver or animal studies, and other studies without disclosing full text were excluded in this study. RESULTS: A total of 29 studies were included. Subjects with ACL injury exhibited a significant increase in MTPS (SMD: 0.34 [95% confidence interval (CI): 0.18, 0.49]; P < .0001) and LTPS (SMD: 0.49 [95% CI: 0.30, 0.68]; P < .00001), but not in the CTPS (SMD: 0.09 [95% CI: -0.10, 0.27]; P = .36), compared with controls. Meanwhile, significant differences in MTPS and LTPS were observed in the male subgroup (SMD: 0.41 [95% CI: 0.20, 0.62]; P = .0001 and SMD: 0.55 [95% CI: 0.26, 0.85]; P = .0002, respectively) but not in the female (SMD: 0.31 [95% CI: -0.02, 0.64]; P = .06 and SMD: 0.26 [95% CI: -0.04, 0.56]; P = .09, respectively). CONCLUSIONS: The present meta-analysis showed that the increases in MTPS and LTPS were overall risk factors of ACL injury. However, these slopes would only be considered as "at risk" for males, but not for females. In addition, it was also proved that CTPS was not a risk factor of ACL injury. LEVEL OF EVIDENCE: Level III, meta-analysis of Level II and III studies.

Long noncoding RNAs in osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis that may affect all joint tissues. Unfortunately, the pathogenesis of OA is not fully understood yet and it cannot be cured totally. Long noncoding RNA (lncRNA) is a type of RNA molecule greater than 200 nucleotides, and deregulated expression of lncRNAs plays an important role in many types of inflammation-related diseases. In this review, we have focused on the association of lncRNAs in the development and progression of OA and the possibility of lncRNAs as a therapeutic agent for the treatment of OA. Some lncRNAs are up-regulated in OA cartilage, and plays a critical role in the degradation of chondrocyte extracellular matrix, consequently weakening the integrity of the articular cartilage. Therapeutic targeting of these lncRNAs has shown significant influence on controlling OA progression. More clinical studies are in focus for OA treatment strategy by targeting lncRNAs.