Extracellular Matrix Metabolism Research Articles

Bauhinia championii alleviates extracellular matrix degradation in IL-1β induced chondrocytes via miRNA-145-5p/TLR4/NF-κB axis

Bauhinia championii is a herbal medicine used to treat osteoarthritis (OA) in Chinese traditional medicine. However, the molecular mechanisms underlying the therapeutic effects of this medicinal herb against OA have rarely been reported. Given that it has been established that extracellular matrix metabolism plays an important role in the pathogenesis of OA, the present study focused on the effects and mechanisms of Bauhinia championii in the regulation of extracellular matrix metabolism in chondrocytes induced by IL-1β. Rat chondrocytes were isolated, cultured and identified in vitro. The CCK-8 method was used to detect the cell viability of Bauhinia championii aqueous extract (BCAE)-treated chondrocytes. The chondrocyte inflammatory and degeneration models were induced by 10 ng/mL IL-1β, then chondrocytes were grouped into different groups to evaluate the effect of BCAE on extracellular matrix degradation and the regulation of TLR4/NF-κB signaling pathway. Furthermore, whether the regulatory effect of BCAE on TLR4/NF-κB signaling pathway is related to miRNA-145-5p was also investigated by cell transfection. We found that BCAE promoted chondrocyte viability in a dose- and time-dependent manner. BCAE delayed chondrocyte degeneration induced by IL-1β. BCAE could reduce the degradation of the cartilage extracellular matrix by inhibiting the TLR4/NF-κB signaling pathway. miRNA-145-5p negatively regulated the expression of TLR4 in chondrocytes, while BCAE could upregulate the expression of miRNA-145-5p in chondrocytes induced by IL-1β. These results suggest that BCAE upregulates the expression of miRNA-145-5p to inhibit the TLR4/NF-κB signaling pathway, thereby alleviating the metabolic imbalance of the extracellular matrix and protecting chondrocytes from degeneration.

An 8-gene predicting survival model of hepatocellular carcinoma (HCC) related to pyroptosis and cuproptosis

BackgroundThe study aimed to establish a prognostic survival model with 8 pyroptosis-and-cuproptosis-related genes to examine the prognostic effect in patients of hepatocellular carcinoma (HCC).MethodsWe downloaded gene expression data and clinical information of HCC patients from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). The clustering analysis and cox regression with LASSO were used for constructing an 8 PCmRNAs survival model. Using TCGA, ICGC and GEO cohort, the overall survival (OS) between high- and low- risk group was determined. We also evaluated independent prognostic indicators using univariate and multivariate analyses. The relatively bioinformatics analysis, including immune cell infiltration, function enrichment and drug sensitivity analyses, was performed as well. The gene expression of 8 PCmRNAs in vitro were validated in several HCC cell lines by qRT-PCR and Western blot. The relationship between GZMA and Fludarabine were further checked by CCK-8 assay.ResultsThe survival prognostic model was constructed with ATP7A, GLS, CDKN2A, BAK1, CHMP4B, NLRP6, NOD1 and GZMA using data from TCGA cohort. The ICGC and GEO cohort were used for model validation. Receiver operating characteristic (ROC) curves showed a good survival prediction by this model. Risk scores had the highest predictable value for survival among Stage, Age, Gender and Grade. Most Immune cells and immune functions were decreased in high-risk group. Besides, function enrichment analyses showed that steroid metabolic process, hormone metabolic process, collagen − containing extracellular matrix, oxidoreductase activity and pyruvate metabolism were enriched. Potential drugs targeted different PCDEGs like Nelarabine, Dexamethasone and Fludarabine were found as well. ATP7A, GLS, CDKN2A, BAK1, CHMP4B, NOD1 were upregulated while NLRP6 and GZMA were downregulated in most HCC cell lines. The potential therapy of Fludarabine was demonstrated when GZMA was low expressed in Huh7 cell line.ConclusionWe constructed a novel 8-gene (ATP7A, GLS, CDKN2A, BAK1, CHMP4B, NLRP6, NOD1 and GZMA) prognostic model and explored potential functional information and microenvironment of HCC, which might be worthy of clinical application. In addition, several potential chemotherapy drugs were screened and Fludarabine might be effective for HCC patients whose GZMA was low expressed.

Endogenous interleukin-22 prevents cardiac rupture after myocardial infarction in mice.

Myocardial infarction (MI) can result in fatal myocardial rupture or heart failure due to adverse remodeling and dysfunction of the left ventricle. Although recent studies have shown that exogenous interleukin (IL)-22 shows cardioprotective effect after MI, the pathophysiological significance of endogenous IL-22 is unknown. In this study, we investigated the role of endogenous IL-22 in a mouse model of MI. We produced MI model by permanent ligation of the left coronary artery in wild-type (WT) and IL-22 knock-out (KO) mice. The post-MI survival rate was significantly worse in IL-22KO mice than in WT mice due to a higher rate of cardiac rupture. Although IL-22KO mice exhibited a significantly greater infarct size than WT mice, there was no significant difference in left ventricular geometry or function between WT and IL-22KO mice. IL-22KO mice showed increase in infiltrating macrophages and myofibroblasts, and altered expression pattern of inflammation- and extracellular matrix (ECM)-related genes after MI. While IL-22KO mice showed no obvious changes in cardiac morphology or function before MI, expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were increased, whereas that of tissue inhibitor of MMPs (TIMP)-3 was decreased in cardiac tissue. Protein expression of IL-22 receptor complex, IL-22 receptor alpha 1 (IL-22R1) and IL-10 receptor beta (IL-10RB), were increased in cardiac tissue 3 days after MI, regardless of the genotype. We propose that endogenous IL-22 plays an important role in preventing cardiac rupture after MI, possibly by regulating inflammation and ECM metabolism.

MicroRNA-224-5p nanoparticles balance homeostasis via inhibiting cartilage degeneration and synovial inflammation for synergistic alleviation of osteoarthritis

MicroRNAs play a crucial role in regulating cartilage extracellular matrix (ECM) metabolism and are being explored as potential therapeutic targets for osteoarthritis (OA). The present study indicated that microRNA-224-5p (miR-224-5p) could balance the homeostasis of OA via regulating cartilage degradation and synovium inflammatory simultaneously. Multifunctional polyamidoamine dendrimer with amino acids used as efficient vector to deliver miR-224-5p. The vector could condense miR-224-5p into transfected nanoparticles, which showed higher cellular uptake and transfection efficiency compared to lipofectamine 3000, and also protected miR-224-5p from RNase degradation. After treatment with the nanoparticles, the chondrocytes showed an increase in autophagy rate and ECM anabolic components, as evidenced by the upregulation of autophagy-related proteins and OA-related anabolic mediators. This led to a corresponding inhibition of cell apoptosis and ECM catabolic proteases, ultimately resulting in the alleviation of ECM degradation. In addition, miR-224-5p also inhibited human umbilical vein endothelial cells angiogenesis and fibroblast-like synoviocytes inflammatory hyperplasia. Integrating the above synergistic effects of miR-224-5p in regulating homeostasis, intra-articular injection of nanoparticles performed outstanding therapeutic effect by reducing articular space width narrowing, osteophyte formation, subchondral bone sclerosis and inhibiting synovial hypertrophy and proliferation in the established mouse OA model. The present study provides a new therapy target and an efficient intra-articular delivery method for improving OA therapy. Statement of significanceOsteoarthritis (OA) is the most prevalent joint disease worldwide. Gene therapy, which involves delivering microRNAs, has the potential to treat OA. In this study, we demonstrated that miR-224-5p can simultaneously regulate cartilage degradation and synovium inflammation, thereby restoring homeostasis in OA gene therapy. Moreover, compared to traditional transfection reagents such as lipofectamine 3000, G5-AHP showed better efficacy in both microRNA transfection and protection against degradation due to its specific surface structure. In summary, G5-AHP/miR-224-5p was developed to meet the clinical needs of OA patients and the high requirement of gene transfection efficiency, providing a promising paradigm for the future application and development of gene therapy.

Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway.

The study aims to explore the medical prospect of melatonin (MLT) and the underlying therapeutic mechanism of MLT-mediated macrophage (Mφ) polarization on the function of nucleus pulposus (NP) in intervertebral disc degeneration (IDD). RAW 264.7 Mφs were induced by lipopolysaccharide (LPS) to simulate Mφ polarization and the inflammatory reaction of Mφs with or without MLT were detected. Conditioned medium (CM) collected from these activated Mφs with or without MLT treatment were further used to incubate NP cells. The oxidative stress, inflammation and extracellular matrix (ECM) metabolism in NP cells were determined. Then, the changes in SIRT1/Notch signaling were detected. The agonist (SRT1720) and inhibitor (EX527) of SIRT1 were used to further explore the association among MLT. The interaction between SIRT1 and NICD was detected by immunoprecipitation (IP). Finally, puncture-induced rat IDD models were established and IDD degrees were clarified by X-ray, MRI, H&E staining and immunofluorescence (IF). The results of flow cytometry and inflammation detection indicated that LPS could induce M1-type Mφ polarization with pro-inflammatory properties. MLT significantly inhibited the aforementioned process and inhibited M1-type Mφ polarization, accompanied by the alleviation of inflammation. Compared with those without MLT, the levels of oxidative stress, pro-inflammatory cytokines and ECM catabolism in NP cells exposed to CM with MLT were markedly downregulated in a dose-dependent manner. The inhibition of SIRT1 and the enhancement of Notch were observed in activated Mφs and they can be reversed after MLT treatment. This prediction was further confirmed by using the SRT1720 and EX527 to activate or inhibit the signaling. The interaction between SIRT1 and NICD was verified by IP. In vivo study, the results of MRI, Pfirrmann grade scores and H&E staining demonstrated the degree of disc degeneration was significantly lower in the MLT-treated groups when compared with the IDD control group. The IF data showed M1-type Mφ polarization decreased after MLT treatment. MLT could inhibit M1-type Mφ polarization and ameliorate the NP cell injury caused by inflammation in vitro and vivo, which is of great significance for the remission of IDD. The SIRT1/Notch signaling pathway is a promising target for MLT to mediate Mφ polarization.

CircRNAs in osteoarthritis: research status and prospect.

Osteoarthritis (OA) is the most common joint disease globally, and its progression is irreversible. The mechanism of osteoarthritis is not fully understood. Research on the molecular biological mechanism of OA is deepening, among which epigenetics, especially noncoding RNA, is an emerging hotspot. CircRNA is a unique circular noncoding RNA not degraded by RNase R, so it is a possible clinical target and biomarker. Many studies have found that circRNAs play an essential role in the progression of OA, including extracellular matrix metabolism, autophagy, apoptosis, the proliferation of chondrocytes, inflammation, oxidative stress, cartilage development, and chondrogenic differentiation. Differential expression of circRNAs was also observed in the synovium and subchondral bone in the OA joint. In terms of mechanism, existing studies have mainly found that circRNA adsorbs miRNA through the ceRNA mechanism, and a few studies have found that circRNA can serve as a scaffold for protein reactions. In terms of clinical transformation, circRNAs are considered promising biomarkers, but no large cohort has tested their diagnostic value. Meanwhile, some studies have used circRNAs loaded in extracellular vesicles for OA precision medicine. However, there are still many problems to be solved in the research, such as the role of circRNA in different OA stages or OA subtypes, the construction of animal models of circRNA knockout, and more research on the mechanism of circRNA. In general, circRNAs have a regulatory role in OA and have particular clinical potential, but further studies are needed in the future.

Recent Therapeutic Strategies for Excessive Chondrocyte Death in Osteoarthritis: A Review.

Osteoarthritis (OA) causes pain and disability in the elderly and has placed a severe burden on healthcare worldwide. Excessive death and decreased density of chondrocytes are recognized as the major pathological characteristic of OA. Chondrocytes have been shown to have multiple forms of death, including apoptosis, pyroptosis, necroptosis, and ferroptosis. The excessive death of chondrocytes often forms a vicious circle with imbalanced chondrocytes extracellular matrix (ECM) metabolism. Therefore, inhibiting chondrocytes excessive death has become a key point that cannot be ignored in the development of OA treatment strategies. We summarized recent studies on the functions and mechanisms of different modes of chondrocyte death and potential therapeutic strategies for OA and offered our views. This may provide direction and theoretical support for formulating OA treatment strategies in the future.

Exosomes derived from mesenchymal stromal cells: a promising treatment for pelvic floor dysfunction.

Pelvic floor dysfunction (PFDs), which include pelvic organ prolapse (POP), stress urinary incontinence (SUI) and anal incontinence (AI), are common degenerative diseases in women that have dramatic effects on quality of life. The pathology of PFDs is based on impaired pelvic connective tissue supportive strength due to an imbalance in extracellular matrix (ECM) metabolism, the loss of a variety of cell types, such as fibroblasts, muscle cells, peripheral nerve cells, and oxidative stress and inflammation in the pelvic environment. Fortunately, exosomes, which are one of the major secretions of mesenchymal stromal cells (MSCs), are involved in intercellular communication and the modulation of molecular activities in recipient cells via their contents, which are bioactive proteins and genetic factors such as mRNAs and miRNAs. These components modify fibroblast activation and secretion, facilitate ECM modelling, and promote cell proliferation to enhance pelvic tissue regeneration. In this review, we focus on the molecular mechanisms and future directions of exosomes derived from MSCs that are of great value in the treatment of PFD.

Evaluation of the main regulators of extracellular matrix metabolism in healthy adolescents in the Far North

Myocardial remodeling is well-known to be both an adaptive option under certain conditions of life (sports, pregnancy, etc.), and the result of cardiovascular pathology. The study of the features of cardiac remodeling includes the involvement of cardiomyocytes in the process by the level of troponins, creatine phosphokinase, and its cardiac isoform as markers of ischemia and necrosis. Also, neurohormonal rearrangement is evaluated using a natriuretic peptide, and endothelial dysfunction is determined using a C–reactive protein. The level of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) reflects the degree of the proteolytic activity and collagen fibers’ degradation. However, there are no clear biochemical markers of “adaptive heart” and pathological changes in different age periods, in the climatic environment, various types and severity of sports loads, especially when evaluating matrix metalloproteinases and their tissue inhibitors. The primary task in determining the criteria for pathological remodeling of the myocardium becomes the definition of normative indicators.The aim of the study was to determine the reference values of the main biochemical markers of cardiac remodeling in healthy adolescents living in the Far North. The levels of troponin I, creatine phosphokinase-MV, aspartate aminotransferase did not exceed the generally accepted standard values. There were correlations between lactate dehydrogenase, aspartate aminotransferase, and mass-growth indicators of adolescents. Markers of extracellular matrix degradation (MMP-9, TIMP-1 and TIMP-4, MMP-9/ TIMP-1) differed from the data available in the published studies, which is probably due to the influence of tissue hypoxia associated with the climatic living conditions and the age in children of the study group.

SPTLC2 ameliorates chondrocyte dysfunction and extracellular matrix metabolism disturbance in vitro and in vivo in osteoarthritis

Disturbances in chondrocyte extracellular matrix (ECM) metabolism in osteoarthritis (OA) are a major cause of OA and potentially lead to personal disability, placing a huge burden on society. Chondrocyte apoptosis and ECM catabolism have a major role in the OA process. Firstly, bioinformatics analysis was performed to screen differentially expressed genes (DEGs) in OA, and serine palmitoyltransferase subunit 2 (SPTLC2) was chosen, which had high-level expression in the OA cartilage tissues and OA chondrocytes. Overexpression and knockdown of SPTLC2 were achieved in OA chondrocytes and normal chondrocytes respectively to study the effect of SPTLC2 upon ECM metabolism of chondrocytes. Cell viability and apoptosis were measured using MTT and flow cytometry analyses; SPTLC2 overexpression enhanced the OA chondrocyte viability and decreased apoptotic rate. In addition, Western blot detection of ECM-related factors (Collagen I, Collage II, MMP-1, MMP-3, and MMP-13) revealed that SPTLC2 overexpression promoted the expression of collagens (Collagen I and Collage II) and suppressed matrix metalloproteinase (MMP-1, MMP-3, and MMP-13) level. In contrast, SPTLC2 knockdown in normal chondrocytes showed opposite effects on cell viability, apoptosis, and ECM degeneration. The articular cartilage of OA rats was transfected with lentivirus overexpressing SPTLC2; HE and Safranin-O fast green demonstrated that SPTLC2 overexpression could alleviate chondrocyte injuries and slow down the development of OA. In conclusion, SPTLC2 plays a role in OA and may be a potential target gene for the treatment of OA.

ScRNA-seq reveals aging-related immune cell types and regulators in vaginal wall from elderly women with pelvic organ prolapse.

In the pathology of pelvic organ prolapse (POP), little is known about the contributing role of pelvic microenvironment. Also, the age-related differences in pelvic microenvironment of POP patients is always ignored. In the present study, we investigated the age-related differences in pelvic microenvironment between Young POP patients and Old POP patients, and the novel cell types and critical regulators which contributes to the age-related differences. Single-cell transcriptomic analyses were used to detect the changes in cell composition and gene expression from the pelvic microenvironment of control group (<60 years), Young POP group (<60 years) and Old POP group (>60 years). Then, immunohistochemistry and immunofluorescence were used to verify the novel cell types and critical regulators in the pelvic microenvironment. Furthermore, histopathological alteration and mechanical property alteration in POP with different ages were revealed by vaginal tissue histology and biomechanical testing. The up-regulated biological process in Old women with POP is mainly related to chronic inflammation, while the up-regulated biological process in Young women with POP is mainly related to extracellular matrix metabolism. Meantime, CSF3+ endothelial cells and FOLR2+ macrophages were found to play a central role in inducing pelvic chronic inflammation. Furthermore, the collagen fiber and mechanical property of POP patients decreased with aging. Taken together, this work provides a valuable resource for deciphering the aging-related immune cell types and the critical regulators in pelvic microenvironment. With better understanding of normal and abnormal events in this pelvic microenvironment, we provided rationales of personalized medicine for POP patients with different ages.

Exosomes from M2c macrophages alleviate intervertebral disc degeneration by promoting synthesis of the extracellular matrix via MiR-124/CILP/TGF-β.

Immuno-inflammation is highly associated with anabolic and catabolic dysregulation of the extracellular matrix (ECM) in the nucleus pulposus (NP), which dramatically propels intervertebral disc degeneration (IVDD). With the characteristics of tissue remodeling and regeneration, M2c macrophages have attracted great attention in research on immune modulation that rebuilds degenerated tissues. Therefore, we first demonstrated the facilitating effects of M2c macrophages on ECM anabolism of the NP in vitro. We subsequently found that exosomes from M2c macrophages (M2c-Exoss) mediated their metabolic rebalancing effects on the ECM. To determine whether M2c-Exoss served as positive agents protecting the ECM in IVDD, we constructed an M2c-Exos-loaded hyaluronic acid hydrogel (M2c-Exos@HA hydrogel) and implanted it into the degenerated caudal disc of rats. The results of MRI and histological staining indicated that the M2c-Exos@HA hydrogel alleviated IVDD in vivo in the long term. To elucidate the underlying molecular mechanism, we performed 4D label-free proteomics to screen dysregulated proteins in NPs treated with M2c-Exoss. Cartilage intermediate layer protein (CILP) was the key protein responsible for the rebalancing effects of M2c-Exoss on ECM metabolism in the NP. With prediction and verification using luciferase assays and rescue experiments, miR-124-3p was identified as the upstream regulator in M2c-Exoss that regulated CILP and consequently enhanced the activity of the TGF-β/smad3 pathway. In conclusion, we demonstrated ameliorating effects of M2c-Exoss on the imbalance of ECM metabolism in IVDD via the miR-124/CILP/TGF-β regulatory axis, which provides a promising theoretical basis for the application of M2c macrophages and their exosomes in the treatment of IVDD.

Nucleus Pulposus Cells from Calcified Discs Promote the Degradation of the Extracellular Matrix through Upregulation of the GATA3 Expression.

Disc calcification is strongly associated with disc degeneration; however, the underlying mechanisms driving its pathogenesis are poorly understood. This study aimed to provide a gene expression profile of nucleus pulposus cells (NPCs) from calcified discs, and clarify the potential mechanism in disc degeneration. Primary NPCs were isolated from calcified and control discs (CAL-NPC and CON-NPC), respectively. The proliferation and extracellular matrix (ECM) metabolism capacities of the cells were evaluated using MTT and Western blotting, respectively. RNA sequencing was used to identify differentially expressed genes (DEGs) in the CAL-NPCs. The biological functions of the DEGs were analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The transcription factor database and Cytoscape software were used to construct the transcription factor-DEGs regulatory network. The role of the verified transcription factor in NPC proliferation and ECM metabolism was also investigated. The CAL-NPCs exhibited a lower proliferation rate and higher ECM degradation capacity than the CON-NPCs. In total, 375 DEGs were identified in the CAL-NPCs. The GO and KEGG analyses showed that the DEGs were primarily involved in the regulation of ribonuclease activity and NF-kappa B and p53 signaling pathways. GATA-binding protein 3 (GATA3) with the highest verified levels was selected for further studies. Overexpression of GATA3 in the CON-NPCs significantly inhibited their proliferation and promoted their ECM degradation function, while the knockdown of GATA3 in the CAL-NPCs resulted in the opposite phenotypes. This study provided a comprehensive gene expression profile of the NPCs from the calcified discs and supported that GATA3 could be a potential target for reversing calcification-associated disc degeneration.

CircZSWIM6 mediates dysregulation of ECM and energy homeostasis in ageing chondrocytes through RPS14 post-translational modification.

Circular RNAs (CircRNAs) are important and have different roles in disease progression. Herein, we aim to elucidate the roles of a novel CircRNA (CircZSWIM6) which is upregulated in ageing chondrocytes. We verified the roles of CircZSWIM6 in senescent and osteoarthritis (OA) development in vitro through CircZSWIM6 knockdown and overexpression. RNA pulldown assay and RNA binding protein immunoprecipitation were performed to identify the interaction between CircZSWIM6 and Ribosomal protein S14 (RPS14). The roles of CircZSWIM6 in ageing-related OA were also confirmed in non-traumatic and traumatic model respectively. CircZSWIM6 regulates extracellular matrix (ECM) and energy metabolism in ageing chondrocyte. Mechanistically, CircZSWIM6 competitively bound to the E3 ligase STUB1 binding site on RPS14 (K125) to inhibit proteasomal degradation of RPS14 to maintain RPS14 function. CircZSWIM6-RPS14 axis is highly associated with AMPK signaling transduction, which keeps energy metabolism in chondrocyte. Furthermore, CircZSWIM6 AAV infection leads to senescent and OA phenotypes in a non-traumatic model and accelerates OA progression in a traumatic model. Our results revealed a significant role of CircZSWIM6 in age-related OA by regulating ECM metabolism and AMPK-associated energy metabolism. We highlight the CircZSWIM6-RPS14-PCK1-AMPK axis is a potential biomarker for OA.

Disc regeneration by injectable fucoidan-methacrylated dextran hydrogels through mechanical transduction and macrophage immunomodulation

Modulating a favorable inflammatory microenvironment that facilitates the recovery of degenerated discs is a key strategy in the treatment of intervertebral disc (IVD) degeneration (IDD). More interestingly, well-mechanized tissue-engineered scaffolds have been proven in recent years to be capable of sensing mechanical transduction to enhance the proliferation and activation of nucleus pulposus cells (NPC) and have demonstrated an increased potential in the treatment and recovery of degenerative discs. Additionally, existing surgical procedures may not be suitable for IDD treatment, warranting the requirement of new regenerative therapies for the restoration of disc structure and function. In this study, a light-sensitive injectable polysaccharide composite hydrogel with excellent mechanical properties was prepared using dextrose methacrylate (DexMA) and fucoidan with inflammation-modulating properties. Through numerous in vivo experiments, it was shown that the co-culture of this composite hydrogel with interleukin-1β-stimulated NPCs was able to promote cell proliferation whilst preventing inflammation. Additionally, activation of the caveolin1-yes-associated protein (CAV1-YAP) mechanotransduction axis promoted extracellular matrix (ECM) metabolism and thus jointly promoted IVD regeneration. After injection into an IDD rat model, the composite hydrogel inhibited the local inflammatory response by inducing macrophage M2 polarization and gradually reducing the ECM degradation. In this study, we propose a fucoidan-DexMA composite hydrogel, which provides an attractive approach for IVD regeneration.

Correction: Selenium-sensitive histone deacetylase 2 is required for forkhead box O3A and regulates extracellular matrix metabolism in cartilage

Correction: Selenium-sensitive histone deacetylase 2 is required for forkhead box O3A and regulates extracellular matrix metabolism in cartilage

METFORMIN AS A PROMISING ANTI-AGING AGENT IN THE TREATMENT OF OSTEOARTHRITIS

Osteoarthritis (OA) is traditionally considered an age-related disease. Therefore, repurposing drugs with the potential to reduce cell senescence is a justified therapeutic strategy. Such is the case of metformin, the most widely used antidiabetic medicine with well-known pharmacokinetics, acceptable toxicity, and beneficial metabolic effects. Metformin could significantly impact processes associated with aging and OA such as cellular senescence, infammaging, mitochondrial dysfunction and impaired nutrient sensing. The aim of the present narrative review is to unveil the potential of metformin to modify disease course in light of aging osteoarthritic joints. The drug has pleiotropic effects on chondrocyte and extracellular matrix metabolism and may provide through AMPK-dependent and -independent pathways a meaningful improvement of OA. Mostly preclinical and retrospective cohort studies have shown that metformin exposure could lead to the regulation of cartilage homeostasis, symptomatic relief of pain and postpone surgery for those suffering from OA. Randomized control trials are warranted to justify the preliminary expectations.

The potential mechanisms and application prospects of non-coding RNAs in intervertebral disc degeneration.

Low back pain (LBP) is one of the most common musculoskeletal symptoms and severely affects patient quality of life. The majority of people may suffer from LBP during their life-span, which leading to huge economic burdens to family and society. According to the series of the previous studies, intervertebral disc degeneration (IDD) is considered as the major contributor resulting in LBP. Furthermore, non-coding RNAs (ncRNAs), mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), can regulate diverse cellular processes, which have been found to play pivotal roles in the development of IDD. However, the potential mechanisms of action for ncRNAs in the processes of IDD are still completely unrevealed. Therefore, it is challenging to consider ncRNAs to be used as the potential therapeutic targets for IDD. In this paper, we reviewed the current research progress and findings on ncRNAs in IDD: i). ncRNAs mainly participate in the process of IDD through regulating apoptosis of nucleus pulposus (NP) cells, metabolism of extracellular matrix (ECM) and inflammatory response; ii). the roles of miRNAs/lncRNAs/circRNAs are cross-talk in IDD development, which is similar to the network and can modulate each other; iii). ncRNAs have been attempted to combat the degenerative processes and may be promising as an efficient bio-therapeutic strategy in the future. Hence, this review systematically summarizes the principal pathomechanisms of IDD and shed light on the therapeutic potentials of ncRNAs in IDD.

Ultraviolet A at levels experienced outdoors suppresses transforming growth factor-beta signaling and collagen production in human scleral fibroblasts

Previous studies have highlighted the importance of outdoor time in reducing the risk of myopia progression. Although ultraviolet A (UVA) radiation dominates in terms of energy with respect to the UV radiation reaching the Earth's surface, its effects on the exposed anterior sclera have not been well studied. This study was designed to investigate the UVA-induced biological effects at peak sunlight levels in human scleral fibroblasts (HSFs). Using next-generation sequencing (NGS), we analyzed the differentially expressed genes (DEGs) in UVA-treated and normal HSFs. Further, we then identified the functions and key regulators of the DEGs using bioinformatics analysis, and verified the effects of UVA on gene and protein expression in HSFs using real-time PCR, western blotting, and immunofluorescence imaging. The highest level of solar UVA (365 nm) was 3.4 ± 0.18 (mW/cm2). The results from the functional analysis of the DEGs were related to structural changes in the extracellular matrix (ECM) and protein metabolism. Transforming growth factor-β1 (TGF-β1) and Smad3 were predicted to be potential upstream regulators, associated with ECM organization. Exposure to a single wavelength of UVA (365 nm, 3 mW/cm2) for 1 h for 5 consecutive days induced the downregulation of the mRNA of ECM genes including COL1A1, COL3A1, COL5A1, VCAN and collagen I protein in HSF. UVA downregulated Smad3 protein and reduced TGF-β-induced collagen I protein production following UVA exposure in HSF. In conclusion, high UVA exposure reduces TGF-β signaling and collagen I production by modulating Smad levels in HSF. The effects of overexposure to high-intensity UVA on myopia control require further investigations.

Dam-Infant Rhesus Macaque Pairs to Dissect Age-Dependent Responses to SARS-CoV-2 Infection.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease (COVID-19) has led to a pandemic of unprecedented scale. An intriguing feature of the infection is the minimal disease in most children, a demographic at higher risk for other respiratory viral diseases. To investigate age-dependent effects of SARS-CoV-2 pathogenesis, we inoculated two rhesus macaque monkey dam-infant pairs with SARS-CoV-2 and conducted virological and transcriptomic analyses of the respiratory tract and evaluated systemic cytokine and Ab responses. Viral RNA levels in all sampled mucosal secretions were comparable across dam-infant pairs in the respiratory tract. Despite comparable viral loads, adult macaques showed higher IL-6 in serum at day 1 postinfection whereas CXCL10 was induced in all animals. Both groups mounted neutralizing Ab responses, with infants showing a more rapid induction at day 7. Transcriptome analysis of tracheal airway cells isolated at day 14 postinfection revealed significant upregulation of multiple IFN-stimulated genes in infants compared with adults. In contrast, a profibrotic transcriptomic signature with genes associated with cilia structure and function, extracellular matrix composition and metabolism, coagulation, angiogenesis, and hypoxia was induced in adults compared with infants. Our study in rhesus macaque monkey dam-infant pairs suggests age-dependent differential airway responses to SARS-CoV-2 infection and describes a model that can be used to investigate SARS-CoV-2 pathogenesis between infants and adults.