Osteonecrosis of the femoral head (ONFH) is a destructive bone disease, and overuse of alcohol is one of the major contributing factors. Although mesenchymal stem cells (MSCs) and their exosomes have been reported to attenuate ONFH, the potential mechanisms of alcohol-induced ONFH (AONFH) are unclear. Here, we isolated and identified human umbilical cord MSCs-derived exosomal (hucMSCs-exos) miR-25-3p. We observed that hucMSCs-exos transferred miR-25-3p into bone marrow stem cells (BMSCs). HucMSCs-exos miR-25-3p increased cell viability, osteogenic differentiation, and inhibited apoptosis of alcohol-treated BMSCs and AONFH rat model. Mechanically, hucMSCs-exos upregulated miR-25-3p expression in BMSCs by repressing miR-25-3p DNA methylation, and DNA methylation inhibitor 5-Aza-2-deoxycytidine (DAC) ameliorated AONFH. Besides, miR-25-3p suppressed gremlin 1 (GREM1) expression, and upregulation of GREM1 restored the inhibition of hucMSCs-exos on AONFH. Therefore, we determined that hucMSCs-exos miR-25-3p alleviated AONFH by inhibiting miR-25-3p DNA methylation and GREM1 expression, which may help identify novel biomarkers, diagnostic and therapeutic targets.

Objective: Dysregulated lipid metabolism enhances the development and advancement of many cancers, including osteosarcoma (OS); however, the underlying mechanisms are still largely unknown. Therefore, this investigation aimed to elucidate novel potential lipid metabolism-related long non-coding RNAs (lncRNAs) that regulate OS development and provide novel signatures for its prognosis and precise treatment. Materials and methods: The GEO datasets (GSE12865 and GSE16091) were downloaded and analyzed using R software packages. Immunohistochemistry (IHC) was used to evaluate protein levels in OS tissues while real-time qPCR was used to measure lncRNA levels, and MTT assays were used to assess OS cell viability. Results: Two lipid metabolism-associated lncRNAs (LM-lncRNAs), small nucleolar RNA host gene 17 (SNHG17) and LINC00837, were identified as efficient and independent prognostic indicators for OS. In addition, further experiments confirmed that SNHG17 and LINC00837 were significantly elevated in OS tissues and cells than para-cancerous counterparts. Knockdown of SNHG17 and LINC00837 synergistically suppressed the viability of OS cells, whereas overexpression of the two lncRNAs promoted OS cell proliferation. Moreover, bioinformatics analysis was conducted to construct six novel SNHG17-microRNA-mRNA competing endogenous RNA (ceRNA) networks, and three lipid metabolism-associated genes (MIF, VDAC2, and CSNK2A2) were found to be abnormally upregulated in OS tissues, suggesting that they were potential effector genes of SNHG17. Conclusion: In summary, SNHG17 and LINC00837 were found to promote OS cell malignancy, suggesting their use as ideal biomarkers for OS prognosis and treatment.

Research shows a close association between aberrant immune reactions in osteonecrotic tissues and immune cell infiltration. However, due to limitations in sample size and dataset comprehensiveness, the causal relationship between them is not fully established. This study aims to determine whether there is a causal relationship using a larger and more diverse dataset. We conducted a comprehensive Mendelian Randomization (MR) analysis to investigate the causal relationship between immune cell characteristics and osteonecrosis. Utilizing publicly available genetic data, we explored the causal relationships between 731 immune cell features and 604 cases from the FinnGen Finnish database, as well as 257 cases from the UK Biobank database with osteonecrosis data. The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. In addition, considering data from the two databases used in this study, a meta-analysis was conducted on the significant immune cells associated with osteonecrosis (FDR <0.05). our findings suggested that specific immune cell signatures, such as CD20⁻ % lymphocytes, CD62L-monocytes, and CD33br HLA DR⁺ CD14⁻cells were associated with increased odds of osteonecrosis. In contrast, EM CD4⁺ activated cells and DP (CD4⁺ CD8⁺) T cells were associated with decreased odds. Notably, osteonecrosis was associated with a potential decrease in CD45 on immature MDSC cell content. From a genetic perspective, we demonstrated a close association between immune cells and osteonecrosis. These findings significantly enhance our understanding of the interplay between immune cell infiltration and the risk of osteonecrosis, contributing to the potential design of therapeutic strategies from an immunological standpoint.