Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases.

Degenerative musculoskeletal diseases are structural and functional failures of the musculoskeletal system, including osteoarthritis, osteoporosis, intervertebral disc degeneration (IVDD), and sarcopenia. As the global population ages, degenerative musculoskeletal diseases are becoming more prevalent. However, the pathogenesis of degenerative musculoskeletal diseases is not fully understood. Previous studies have revealed that endoplasmic reticulum (ER) stress is a stress response that occurs when impairment of the protein folding capacity of the ER leads to the accumulation of misfolded or unfolded proteins in the ER, contributing to degenerative musculoskeletal diseases. By affecting cartilage degeneration, synovitis, meniscal lesion, subchondral bone remodeling of osteoarthritis, bone remodeling and angiogenesis of osteoporosis, nucleus pulposus degeneration, annulus fibrosus rupture, cartilaginous endplate degeneration of IVDD, and sarcopenia, ER stress is involved in the pathogenesis of degenerative musculoskeletal diseases. Preclinical studies have found that regulation of ER stress can delay the progression of multiple degenerative musculoskeletal diseases. These pilot studies provide foundations for further evaluation of the feasibility, efficacy, and safety of ER stress modulators in the treatment of musculoskeletal degenerative diseases in clinical trials. In this review, we have integrated up-to-date research findings of ER stress into the pathogenesis of degenerative musculoskeletal diseases. In a future perspective, we have also discussed possible directions of ER stress in the investigation of degenerative musculoskeletal disease, potential therapeutic strategies for degenerative musculoskeletal diseases using ER stress modulators, as well as underlying challenges and obstacles in bench-to-beside research.

The p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop mediates vasoactive intestinal peptide effects on osteoarthritis chondrocytes.

Loss and dysfunction of articular chondrocytes, which disrupt the homeostasis of extracellular matrix formation and breakdown, promote the onset of osteoarthritis (OA). Targeting inflammatory pathways is an important therapeutic strategy for OA. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide with potent anti-inflammatory effects; however, its role and mechanism in OA remain unclear. In this study, microarray expression profiling from the Gene Expression Omnibus database and integrative bioinformatics analyses were performed to identify differentially expressed lncRNAs in OA samples. qRT-PCR validation of the top ten different expressed lncRNAs indicated that the expression level of intergenic non-protein coding RNA 2203 (LINC02203, also named LOC727924) was the highest in OA cartilage compared to normal cartilage. Hence, the LOC727924 function was further investigated. LOC727924 was upregulated in OA chondrocytes, with a dominant sub-localization in the cytoplasm. In OA chondrocytes, LOC727924 knockdown boosted cell viability, suppressed cell apoptosis, reactive oxygen species (ROS) accumulation, increased aggrecan and collagen II, decreased matrix metallopeptidase (MMP)-3/13 and ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)-4/5 levels, and reduced the levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6). LOC727924 could interact with the microRNA 26a (miR-26a)/ karyopherin subunit alpha 3 (KPNA3) axis by competitively targeting miR-26a for KPNA3 binding, therefore down-regulating miR-26a and upregulating KPNA3; in OA chondrocytes, miR-26a inhibition partially abolished LOC727924 knockdown effects on chondrocytes. miR-26a inhibited the nuclear translocation of p65 through targeting KPNA3 and p65 transcriptionally activated LOC727924, forming a p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop to modulate OA chondrocyte phenotypes. In vitro, VIP improved OA chondrocyte proliferation and functions, down-regulated LOC727924, KPNA3, and p65 expression, and upregulated miR-26a expression; in vivo, VIP ameliorated destabilization of the medial meniscus (DMM)-induced damages on the mouse knee joint, down-regulated KPNA3, inhibited the nuclear translocation of p65. In conclusion, the p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop modulates OA chondrocyte apoptosis, ROS accumulation, extracellular matrix (ECM) deposition, and inflammatory response in vitro and OA development in vivo, being one of the mechanisms mediating VIP ameliorating OA.

Endoplasmic Reticulum Stress in Osteoarthritis: A Novel Perspective on the Pathogenesis and Treatment.

Osteoarthritis (OA), the most common degenerative joint disease, causes an enormous socioeconomic burden due to its disabling properties and high prevalence. Increasing evidence suggests that OA is a whole-joint disease involving cartilage degradation, synovitis, meniscal lesions, and subchondral bone remodeling. Endoplasmic reticulum (ER) stress is the accumulation of misfolded/unfolded proteins in the ER. Recent studies have found that ER stress is involved in the OA pathological changes by influencing the physiological function and survival of chondrocytes, fibroblast-like synoviocytes, synovial macrophages, meniscus cells, osteoblasts, osteoclasts, osteocytes, and bone marrow mesenchymal stem cells. Therefore, ER stress is an attractive and promising target for OA. However, although targeting ER stress has been proven to alleviate OA progression in vitro and in vivo, the treatments for OA remain in preclinical stage and require further investigation.

Development and validation of a novel immune-related prognostic signature in lung squamous cell carcinoma patients.

Lung Squamous Cell Carcinoma (LUSC) is an aggressive malignancy with limited therapeutic options. The response to immune therapy is a determining factor for the prognosis of LUSC patients. This study aimed to develop a reliable immune-related prognostic signature in LUSC. We extracted gene expression and clinical data of LUSC from The Cancer Genome Atlas (TCGA). A total of 502 patients enrolled and were divided into respond and non-responder groups by the TIDE algorithm. The CIBERSORT algorithm and the LM22 gene signature were used to analyze the distribution of immune cells in LUSC. Efficacy and response strength of immunotherapy are calculated by the tumor mutation burden (TMB) and ESTIMATE Score. Differentially expressed genes (DEGs) between the two groups were analyzed. The differential expression genes related to overall survival were pointed as hub DEGs, and a prognostic signature was constructed with lasso regression analysis. LUSC patients were divided into responder and non-responder groups based on the response to immunotherapy. The distribution of immune cells was significantly different between the two groups. Forty-four DGEs were considered as overall survival-related genes. A prognostic signature was constructed, consisting of 11 hub-DGEs, including MMP20, C18orf26, CASP14, FAM71E2, OPN4, CGB5, DIRC1, C9orf11, SPATA8, C9orf144B, and ZCCHC5. The signature can accurately distinguish LUSC patients into high and low-risk groups. Moreover, the high-risk group had a shorter survival time than the low-risk group. The area under the ROC curve was 0.67. The multivariate Cox regression showed that the risk score calculated by the constructed signature was an independent prognostic predictor for LUSC patients. In short, we established a novel immune-related prognostic signature in LUCS, which has significant sensitivity and accuracy in predicting the prognosis of patients. Our research can guide the evaluation of the prognosis of LUSC patients in clinical, and the discovered immune-related genes can provide a theoretical basis for the discovery of new therapeutic targets.

Recognition of immune-related tumor antigens and immune subtypes for mRNA vaccine development in lung adenocarcinoma.

Background: There are currently no treatments targeting the immune microenvironment (TME) as an extension of immunotherapy. Our research aims to provide guidance for the development of immune-related mRNA vaccines and the identification of immune subtypes for vaccine treatment in lung adenocarcinoma (LUAD). Methods: HTRNA-Seq and single cell RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO, GSE87340, GSE140343, GSE148071) databases. Immune checkpoints (ICP) were used as criteria to differentiate immune subtypes and immune resistance score (IRS) system is constructed by ssGSEA to judge the immune microenvironment status of patients. Results: Two overexpressed tumor-specific antigens, including ZC3H12D and TXNDC5, were found to be associated with both disease-free survival (DFS) and overall survival (OS). In addition, the expression of two genes correlated with antigen-presenting cell (APC) infiltration and tumor purity. Subsequently, the immune subtype of the patient was defined by constructing an IRS scoring system. The lower the IRS, the stronger the immune response in the TME. This result was verified in external datasets and at the single-cell level. Conclusions: ZC3H12D and TXNDC5 are potential tumor-specific antigens for developing mRNA vaccines in LUAD. Importantly, patients with low IRS are more suitable for the use of immunotherapy and vaccines. Our research enhances understanding of TME features and guides more effective immunotherapy strategies.

Extracellular Vesicles in the Progression and Therapeutic Resistance of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy largely associated with Epstein-Barr virus (EBV) infection, which is frequently reported in east and southeast Asia. Extracellular vesicles (EVs) originate from the endosome or plasma membrane, which plays a critical role in tumor pathogenesis for their character of cell-cell communication and its cargos, including proteins, RNA, and other molecules that can target recipient cells and affect their progression. To date, numerous studies have indicated that EVs have crucial significance in the progression, metastasis, and therapeutic resistance of NPC. In this review, we not only summarize the interaction of NPC cells and the tumor microenvironment (TME) through EVs, but also explain the role of EVs in radiation and drug resistance of NPC, which poses a severe threat to cancer therapy. Therefore, EVs may show great potential as biomarkers in the early diagnosis of interfered targets of NPC therapy.