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 role of circadian clock genes in colorectal carcinoma: Novel insights into regulatory mechanism and implications in clinical therapy.

Colorectal cancer (CRC) is a lethal malignancy with limited treatment strategies. Accumulating evidence indicates that CRC tumorigenesis, progression and metastasis are intimately associated with circadian clock, an inherent 24-h cycle oscillation of biochemical, physiological functions in almost every eukaryote. In the present review, we summarize the altered expression level of circadian genes in CRC and the prognosis associated with gene abundance switch. We illustrate the function and potential mechanisms of circadian genes in CRC pathogenesis and progression. Moreover, circadian based-therapeutic strategies including chronotherapy, therapeutics targeting potential circadian components, and melatonin treatment in CRC are also highlighted.

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.

The miR-548d-5p/SP1 signaling axis regulates chondrocyte proliferation and inflammatory responses in osteoarthritis.

Chondrocyte apoptosis and dysfunction play an important role in osteoarthritis (OA), a chronic progressive arthropathy. Non-coding RNAs have been implicated in OA pathogenesis. In this study, microRNA (miR)-548d-5p was found to be downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p overexpression partially reversed IL-1ß-induced chondrocyte damage in vitro, evidenced by the promotion of cell growth, the inhibition of apoptosis and inflammatory cytokine release, and the improvement in extracellular matrix (ECM) deposition. Furthermore, miR-548d-5p overexpression partially reversed papain-induced damages on OA rat's knee articular cartilage. Specificity protein 1 (SP1) was inhibited by miR-548d-5p and identified as its direct downstream target. In IL-1ß-stimulated chondrocytes, SP1 overexpression significantly attenuated the protective effects of miR-548d-5p overexpression against chondrocyte damage. In conclusion, miR-548d-5p was abnormally downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p protects against IL-1ß-induced chondrocyte damage via direct inhibition of SP1.

Global Trends and Current Status in Osteonecrosis of the Femoral Head: A Bibliometric Analysis of Publications in the Last 30 Years.

Introduction: Osteonecrosis of the femoral head (ONFH) is a progressive and disabling disease with severe socioeconomic burdens. In the last 30 years, a growing number of publications have reported significant advances in understanding ONFH. However, only a few studies have clarified its global trends and current status. Thus, the purpose of our study was to summarize the global trends and current status in ONFH through bibliometrics. Materials and Methods: Publications related to ONFH from 1991 to 2020 were searched from the Web of Science (WOS) core collection database. The data were analyzed with bibliometric methods. Microsoft Excel was used for statistical analysis and to draw bar charts. SPSS was applied to perform linear regression analysis. VOSviewer was used to conduct bibliographic coupling analysis, co-authorship analysis, co-citation analysis and co-occurrence analysis. Results: A total of 5,523 publications were covered. The United States consistently ranked first in total publications, sum of times cited, average citations per item and H-index. Kyushu University was the main contributor to ONFH. Clinical Orthopaedics and Related Research was the major publishing channels for ONFH-related articles. Takuaki Yamamoto published the most ONFH-related articles. Studies regarding ONFH could be divided into five clusters: 1) mechanism study, 2) treatment study, 3) complication study, 4) radiological study and 5) etiological study. Mechanism study might become a hot spot in the future. Conclusions: The total number of publications in ONFH has generally increased over the last three decades. The United States was the leading country in ONFH research. Transplantation, engineering, cell and molecular biology, pharmacology and endocrinology have gradually increased and become hot topics in ONFH research. Mechanism study in ONFH including mesenchymal stem cells, apoptosis, oxidative stress, adipogenesis, osteogenic differentiation and endothelial progenitor cells, have attracted more attention and will become a hot spot in the future.

Steroid-Induced Osteonecrosis of the Femoral Head: Novel Insight Into the Roles of Bone Endothelial Cells in Pathogenesis and Treatment.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a disease characterized by the collapse of the femoral head. SONFH occurs due to the overuse of glucocorticoids (GCs) in patients with immune-related diseases. Among various pathogenesis proposed, the mechanism related to impaired blood vessels is gradually becoming the most convincing hypothesis. Bone endothelial cells including bone microvascular endothelial cells (BMECs) and endothelial progenitor cells (EPCs) play a crucial role in the maintenance of vascular homeostasis. Therefore, bone endothelial cells are key regulators in the occurrence and progression of SONFH. Impaired angiogenesis, abnormal apoptosis, thrombosis and fat embolism caused by the dysfunctions of bone endothelial cells are considered to be the pathogenesis of SONFH. In addition, even with high disability rates, SONFH lacks effective therapeutic approach. Icariin (ICA, a flavonoid extracted from Epimedii Herba), pravastatin, and VO-OHpic (a potent inhibitor of PTEN) are candidate reagents to prevent and treat SONFH through improving above pathological processes. However, these reagents are still in the preclinical stage and will not be widely used temporarily. In this case, bone tissue engineering represented by co-transplantation of bone endothelial cells and bone marrow mesenchymal stem cells (BMSCs) may be another feasible therapeutic strategy.

G Protein-Coupled Receptors in Osteoarthritis: A Novel Perspective on Pathogenesis and Treatment.

G protein-coupled receptors (GPCRs) are transmembrane receptor proteins that trigger numerous intracellular signaling pathways in response to the extracellular stimuli. The GPCRs superfamily contains enormous structural and functional diversity and mediates extensive biological processes. Until now, critical roles have been established in many diseases, including osteoarthritis (OA). Existing studies have shown that GPCRs play an important role in some OA-related pathogenesis, such as cartilage matrix degradation, synovitis, subchondral bone remodeling, and osteophyte formation. However, current pharmacological treatments are mostly symptomatic and there is a paucity of disease-modifying OA drugs so far. Targeting GPCRs is capable of inhibiting cartilage matrix degradation and synovitis and up-regulating cartilage matrix synthesis, providing a new therapeutic strategy for OA. In this review, we have comprehensively summarized the structures, biofunctions, and the novel roles of GPCRs in the pathogenesis and treatment of OA, which is expected to lay the foundation for the development of novel therapeutics against OA. Even though targeting GPCRs may ameliorate OA progression, many GPCRs-related therapeutic strategies are still in the pre-clinical stage and require further investigation.

Novel Insights Into the Multifaceted Functions of RNA n6-Methyladenosine Modification in Degenerative Musculoskeletal Diseases.

N6-methyladenosine (m6A) is an important modification of eukaryotic mRNA. Since the first discovery of the corresponding demethylase and the subsequent identification of m6A as a dynamic modification, the function and mechanism of m6A in mammalian gene regulation have been extensively investigated. "Writer", "eraser" and "reader" proteins are key proteins involved in the dynamic regulation of m6A modifications, through the anchoring, removal, and interpretation of m6A modifications, respectively. Remarkably, such dynamic modifications can regulate the progression of many diseases by affecting RNA splicing, translation, export and degradation. Emerging evidence has identified the relationship between m6A modifications and degenerative musculoskeletal diseases, such as osteoarthritis, osteoporosis, sarcopenia and degenerative spinal disorders. Here, we have comprehensively summarized the evidence of the pathogenesis of m6A modifications in degenerative musculoskeletal diseases. Moreover, the potential molecular mechanisms, regulatory functions and clinical implications of m6A modifications are thoroughly discussed. Our review may provide potential prospects for addressing key issues in further studies.