Background: Circular RNAs (circRNAs) are involved in diverse processes that drive cancer development. However, the expression landscape and mechanistic function of circRNAs in osteosarcoma (OS) remain to be studied. Methods: Bioinformatic analysis and high-throughput RNA sequencing tools were employed to identify differentially expressed circRNAs between OS and adjacent noncancerous tissues. The expression level of circ_001422 in clinical specimens and cell lines was measured using qRT-PCR. The association of circ_001422 expression with the clinicopathologic features of 55 recruited patients with OS was analyzed. Loss- and gain-of-function experiments were conducted to explore the role of circ_001422 in OS cells. RNA immunoprecipitation, fluorescence in situ hybridization, bioinformatics database analysis, RNA pulldown assays, dual-luciferase reporter assays, mRNA sequencing, and rescue experiments were conducted to decipher the competitive endogenous RNA regulatory network controlled by circ_001422. Results: We characterized a novel and abundant circRNA, circ_001422, that promoted OS progression. Circ_001422 expression was dramatically increased in OS cell lines and tissues compared with noncancerous samples. Higher circ_001422 expression correlated with more advanced clinical stage, larger tumor size, higher incidence of distant metastases and poorer overall survival in OS patients. Circ_001422 knockdown markedly repressed the proliferation and metastasis and promoted the apoptosis of OS cells in vivo and in vitro, whereas circ_001422 overexpression exerted the opposite effects. Mechanistically, competitive interactions between circ_001422 and miR-195-5p elevated FGF2 expression while also initiating PI3K/Akt signaling. These events enhanced the malignant characteristics of OS cells. Conclusions: Circ_001422 accelerates OS tumorigenesis and metastasis by modulating the miR-195-5p/FGF2/PI3K/Akt axis, implying that circ_001422 can be therapeutically targeted to treat OS.

Osteoporosis, primarily characterized by low bone mineral density (LBMD), is a major skeletal disorder among postmenopausal women (PMW), yet its global burden remains poorly quantified. Leveraging data from the Global Burden of Disease (GBD) Study 2021, we assessed the LBMD burden in PMW across 204 countries and territories between 1990 and 2021. Metrics included deaths, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs), with temporal trends evaluated via estimated annual percentage change (EAPC). We found that in 2021, LBMD was responsible for 219,552 deaths and 7.76 million DALYs in PMW globally, with age-standardized DALY rates reaching 979.2 per 100,000 population. Compared to premenopausal women, PMW experienced a 15.17-fold higher mortality, a 5.84-fold higher burden in DALYs, and a 6.29-fold higher burden in YLDs. While age-standardized rates (ASR) for deaths and DALYs showed slight declines from 1990 to 2021, the absolute number of LBMD-related deaths more than doubled, increasing from 91,941 in 1990 to 219,552 in 2021, largely driven by global population aging. South Asia experienced the greatest burden, with India reporting the highest DALYs rates. The burden was highest in women aged ≥80 years and increased most rapidly in those aged ≥95. Regions with a high Socio-demographic Index (SDI) exhibited lower mortality rates but disproportionately higher levels of disability, whereas low-SDI regions bore a greater burden of mortality. Projections to 2045 suggest a sustained rise in deaths and disability, despite modest rate reductions. These findings underscore the urgent need for age-tailored, equity-focused interventions to mitigate fracture risk and improve musculoskeletal health among aging female populations worldwide.

Osteosarcoma (OSA), the most common primary bone malignancy, poses significant challenges due to its aggressive nature and propensity for metastasis, especially in adolescents. Mitophagy analysis can help identify new therapeutic targets and combined treatment strategies. This study integrates single-cell sequencing (scRNA-seq) data and bulk-seq to identify mitophagy-related genes (MRGs) associated with the progression of OSA metastasis and analyze their clinical significance. scRNA-seq data elucidates the relationship between mitophagy and OSA metastasis, employing “CellChat” R package to explore intercellular communications and report on hundreds of ligand-receptor interactions. Subsequently, the combination of bulk-seq and CRISPR-Cas9 gene editing identifies mitophagy-related biomarker associated with metastatic prognosis. Finally, validation of the relationship between mitophagy and OSA metastasis is achieved through cellular biology experiments and animal studies. The distinct mitophagy activity of various mitochondria manifests in diverse spatial localization, cellular developmental trajectories, and intercellular interactions. OSA tissue exhibits notable heterogeneity in mitophagy within osteoblastic OSA cells. However, high mitophagy activity correlates consistently with high metastatic potential. Subsequently, we identified three critical genes associated with mitophagy in OSA, namely RPS27A, TOMM20 and UBB. According to the aforementioned queue of genes, we have constructed a mitophagy_score (MIP_score). We observed that it consistently predicts patient prognosis in both internal and external datasets, demonstrating strong robustness and stability. Furthermore, we have found that MIP_score can also guide chemotherapy, with varying sensitivities to chemotherapeutic agents based on different MIP_score. It is noteworthy that, through the integration of CRISPR-Cas9 genome-wide screening and validation via cellular and animal experiments, we have identified RPS27A as a potential novel biomarker for OSA. Our comprehensive analysis elucidated the profile of mitophagy throughout the OSA metastasis process, forming the basis for a mitophagy-related prognostic model that addresses clinical outcomes and drug sensitivity following OSA metastasis. Additionally, an online interactive platform was established to assist clinicians in decision-making ( https://mip-score.shinyapps.io/labtan/ ). These findings lay the groundwork for developing targeted therapies aimed at improving the prognosis of OSA patients.

Objectives: We aimed to examine whether metformin (MET) use is associated with a reduced risk of total knee arthroplasty (TKA) and low severity of knee pain in patients with knee osteoarthritis (OA) and diabetes and/or obesity. Methods: Participants diagnosed with knee OA and diabetes and/or obesity from June 2000 to July 2019 were selected from the information system of a local hospital. Regular MET users were defined as those with recorded prescriptions of MET or self-reported regular MET use for at least 6 months. TKA information was extracted from patients’ surgical records. Knee pain was assessed using the numeric rating scale. Log-binomial regression, linear regression, and propensity score weighting (PSW) were performed for statistical analyses. Results: A total of 862 participants were included in the analyses. After excluding missing data, there were 346 MET non-users and 362 MET users. MET use was significantly associated with a reduced risk of TKA (prevalence ratio: 0.26, 95% CI: 0.15 to 0.45, p < 0.001), after adjustment for age, gender, body mass index, various analgesics, and insurance status. MET use was significantly associated with a reduced degree of knee pain after being adjusted for the above covariates (β: −0.48, 95% CI: −0.91 to −0.05, p = 0.029). There was a significantly accumulative effect of MET use on the reduced risk of TKA. Conclusion: MET can be a potential therapeutic option for OA. Further clinical trials are needed to determine if MET can reduce the risk of TKA and the severity of knee pain in metabolic-associated OA patients.

Although the combination of surgery and chemotherapy has dramatically improved the prognosis of patients with osteosarcoma (OS), the prognosis of OS patients with metastatic or recurrent tumors remains poor. Here, we found significant upregulation of the acetyl-CoA synthesis-related pathway in OS patients with metastases. Bioinformatics analysis identified ACSS1 as a key metastasis-related gene in OS, with clinical OS specimens validating its association with poor prognosis. In vitro, ACSS1 knockdown in 143B and SJSA1 cells was used to assess proliferation (EdU, colony formation), migration/invasion (Transwell, 3D spheroids), and mitochondrial function (Seahorse, TEM). Untargeted metabolomics and transcriptomics characterized ACSS1-regulated lipid pathways, while in vivo validation employed nude mouse models of orthotopic xenograft and tail vein metastasis. Notably, the expression of Acetyl-coenzyme A synthetase 1 (ACSS1), an enzyme critical for acetyl-CoA synthesis, was negatively correlated with pulmonary metastasis-free and overall survival in OS patients. ACSS1 depletion decreases the metastatic ability and energy metabolism of OS cells, resulting in reactive oxygen species (ROS) accumulation. Mechanistically, ACSS1 exerts acetyl-CoA synthetase activity and maintains dynamic homeostasis of acetyl-CoA metabolism in the mitochondria. It promotes lipid synthesis and regulates metabolic homeostasis by inducing stearoyl coenzyme A desaturase (SCD) expression, which can fuel the metastasis of OS cells and promotes their survival. ACSS1 drives OS metastasis by maintaining mitochondrial acetyl-CoA homeostasis and activating SCD-dependent lipid synthesis. Targeting the ACSS1/SCD axis offers a promising strategy for metastatic OS. This study reveals the therapeutic potential of targeting ACSS1/SCD axis, for example, by specific small-molecule inhibitors in treating osteosarcoma metastasis, in addition to conventional chemotherapies.