Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Dihydrotanshinone I protects human chondrocytes and alleviates damage from spontaneous osteoarthritis in a guinea pig model.

Osteoarthritis (OA) is the most common degenerative joint disease. Currently, no satisfactory pharmacological treatment exists for OA. The potential anti-inflammatory properties of Dihydrotanshinone I (DHT) have been reported, but its effects on OA are unclear. In this study, we assess the impact of DHT on the viability of human chondrocytes in vitro. We then use a guinea pig model to investigate the effects of DHT on knee osteoarthritis progression. Twelve-week-old Dunkin Hartley guinea pigs spontaneously developing OA were intraperitoneally injected with different doses of DHT for eight weeks. Micro-CT analysis was performed on the subchondral bone in the knee, and histological assessment of the knee joint was done using stained sections, the ratio of hyaline to calcified cartilage, and Mankin scores. DHT successfully restored IL-1ß-induced decreases in cell viability in human primary chondrocytes. In the guinea pig model, intraperitoneal injections of DHT ameliorated age-induced OA, effectively reduced the expression level of two cartilage metabolism-related genes (ADAMTS4 and MMP13) and decreased the inflammatory biomarker IL-6 in the serum of guinea pigs developing spontaneous osteoarthritis. These findings demonstrate DHT's protective effects on chondrocytes and suggest that it alleviates cartilage degradation and proteoglycan loss in OA.

Which is the most effective one in knee osteoarthritis treatment from mesenchymal stem cells obtained from different sources?-A systematic review with conventional and network meta-analyses of randomized controlled trials.

BACKGROUND: Due to varying degrees of difficulty in obtaining different mesenchymal stem cells (MSCs), the distinct pain levels and treatment costs, and for providing concrete evidence for future clinical practice, a thorough comparison of all relevant MSCs remained critical. Hence, this study aimed to achieve this objective to compare the efficacy of MSCs obtained from different sources in clinical outcomes and cartilage repair of knee osteoarthritis (KOA). METHODS: The EmBase, PubMed and Cochrane Library databases were searched for eligible studies. Randomized controlled trials (RCTs) that compared MSCs from different sources with placebo or each other in KOA patients. Conventional meta-analysis and frequentist network meta-analysis (NMA) were conducted. The primary clinical outcome was pain relief. The frequentist NMA was conducted using Stata with the "network" command. RESULTS: Eight studies (seven trials) involving 203 KOA patients were included in this meta-analysis. The MSCs were considered superior over placebo for pain relief and improved function in KOA, but showed no statistically significant differences for cartilage regeneration. Among all the MSCs, the adipose tissue-derived MSCs (AD-MSCs) most effectively relieved pain. CONCLUSION: These findings suggested that MSCs are effective in the treating of KOA. AD-MSCs might be the most effective for relieving pain, and Umbilical cord-derived mesenchymal stem cells (UC-MSCs) might be the most effective for improving function. However, the current evidence does not support the use of MSCs for improving cartilage repair in KOA patients.

Low­calorie sweetener D­psicose promotes hydrogen peroxide­mediated apoptosis in C2C12 myogenic cells favoring skeletal muscle cell injury.

Diet and exercise are the most effective approaches used to induce weight loss. D­psicose is a low­calorie sweetener that has been shown to reduce weight in obese individuals. However, the effect of D­psicose on muscle cells under oxidative stress, which is produced during exercise, requires further investigation. The present study aimed to determine the effects of D­psicose on C2C12 myogenic cells in vitro. Hydrogen peroxide (H2O2) was used to stimulate the generation of intracellular reactive oxygen species (ROS) in muscle cells to mimic exercise conditions. Cell viability was analyzed using a MTT assay and flow cytometry was used to analyze the levels of apoptosis, mitochondrial membrane potential (MMP), the generation of ROS and the cell cycle distribution following treatment. Furthermore, protein expression levels were analyzed using western blotting and cell proliferation was determined using a colony formation assay. The results of the present study revealed that D­psicose alone exerted no toxicity on C2C12 mouse myogenic cells. However, in the presence of low­dose (100 µM) H2O2­induced ROS, D­psicose induced C2C12 cell injury and significantly decreased C2C12 cell viability in a dose­dependent manner. In addition, the levels of apoptosis and the generation of ROS increased, while the MMP decreased. MAPK family molecules were also activated in a dose­dependent manner following treatment. Notably, the combined treatment induced G2/M phase arrest and reduced the proliferation of C2C12 cells. In conclusion, the findings of the present study suggested that D­psicose may induce toxic effects on muscle cells in a simulated exercise situation by increasing ROS levels, activating the MAPK signaling pathway and disrupting the MMP.