Damaged deoxyribonucleic acid (DNA) is a primary pathologic factor for osteoarthritis (OA); however, the mechanism by which DNA damage drives OA is unclear. Previous research demonstrated that the ...cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) participates in DNA damage response. As a result, the current study aimed at exploring the role STING, which is the major effector in the cGAS-STING signaling casacde, in OA progress in vitro, as well as in vivo. In this study, the expression of STING was evaluated in the human and mouse OA tissues, and in chondrocytes exposed to interleukin-1 beta (IL-1β). The influences of STING on the metabolism of the extracellular matrix (ECM), apoptosis, and senescence, were assessed in STING overexpressing and knocking-down chondrocytes. Moreover, the NF-κB-signaling casacde and its role in the regulatory effects of STING on ECM metabolism, apoptosis, and senescence were explored. The STING knockdown lentivirus was intra-articularly injected to evaluate its therapeutic impact on OA in mice in vivo. The results showed that the expression of STING was remarkably elevated in the human and mouse OA tissues and in chondrocytes exposed to IL-1β. Overexpression of STING promoted the expression of MMP13, as well as ADAMTS5, but suppressed the expression of Aggrecan, as well as Collagen II; it also enhanced apoptosis and senescence in chondrocytes exposed to and those untreated with IL-1β. The mechanistic study showed that STING activated NF-κB signaling cascade, whereas the blockage of NF-κB signaling attenuated STING-induced apoptosis and senescence, and ameliorated STING-induced ECM metabolism imbalance. In in vivo study, it was demonstrated that STING knockdown alleviated destabilization of the medial meniscus-induced OA development in mice. In conclusion, STING promotes OA by activating the NF-κB signaling cascade, whereas suppression of STING may provide a novel approach for OA therapy.
Mesenchymal stem cells (MSCs) have gained increasing attention as a potential approach for the treatment of bone injuries due to their multi-lineage differentiation potential and also their ability ...to recognize and home to damaged tissue sites, secreting bioactive factors that can modulate the immune system and enhance tissue repair. However, a wide gap between the number of MSCs obtainable from the donor site and the number required for implantation, as well as the lack of understanding of MSC functions under different in vitro and in vivo microenvironment, hinders the progression of MSCs toward clinical settings. The clinical translation of MSCs pre-requisites a scalable expansion process for the biomanufacturing of therapeutically qualified cells. This review briefly introduces the features of implanted MSCs to determine the best strategies to optimize their regenerative capacity, as well as the current MSC implantation for bone diseases. Current achievements for expansion of MSCs using various culturing methods, bioreactor technologies, biomaterial platforms, as well as microtissue-based expansion strategies are also discussed, providing new insights into future large-scale MSC expansion and clinical applications.
The blockage of autophagic flux in chondrocytes has been considered as a major reason for the excessive cellular apoptosis and senescence in osteoarthritis (OA) development; however, the molecular ...mechanism and therapeutic strategy for interrupted autophagic flux is still not clear. Most recently, the transcription factor EB (TFEB) is identified as a master regulator for autophagic flux via initiating the expression of multiple autophagy-related genes and lysosomal biogenesis. This research was performed to confirm whether TFEB expression and activity are impacted in OA development and to confirm the effect of genetic up-regulation of TFEB on autophagic flux and cellular protection in the in vitro and in vivo models of OA. We demonstrated that the expression and nuclear localization of TFEB is decreased in human and mouse OA cartilage as well as in tert-Butyl hydroperoxide (TBHP)-treated chondrocytes. Applying lentivirus to transfect chondrocytes, we found that TFEB overexpression rescues the TBHP-induced the autophagic flux damage, lysosome dysfunction and protects chondrocyte against TBHP induced apoptosis and senescence; these protections of TFEB are diminished by chloroquine-medicated autophagy inhibition. Our destabilized medial meniscus (DMM) mouse OA model shows that TFEB overexpression ameliorates the surgery-induced cartilage degradation, restrains the apoptosis and senescence of chondrocyte, and enhances the autophagic flux. In summary, our study indicates that the activity of TFEB in chondrocyte is involved in OA development, also TFEB overexpression may be a promising strategy for OA treatment.
The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the ...subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA.
Well-crystallized α-calcium sulfate hemihydrate (α-CSH) powders useful for bone defect filling were synthesized using a salt solution method and their morphologies were effectively modified by ...adjusting the pH of the reaction solutions or by adding succinic acid. The effect and its mechanism of the pH and the succinic acid on the phase composition and the morphology of the crystals were discussed in detail.
•The effect of pH and succinic acid on the formation and the morphology of α-CSH were studied.•The pH determines the dissolution of CSD crystal and thus changes the supersaturation of Ca2+.•The carboxyl groups from ionized succinic acid can modify the grain growth habit.
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) offer promising prospects for stimulating cartilage regeneration. The different formation mechanisms suggest that exosomes ...and ectosomes possess different biological functions. However, little attention has been paid to the differential effects of EV subsets on cartilage regeneration.
Our study compared the effects of the two EVs isolated from adipose-derived MSCs (ASCs) on chondrocytes and bone marrow-derived MSCs (BMSCs) in vitro. Additionally, we loaded the two EVs into type I collagen hydrogels to optimize their application for the treatment of osteochondral defects in vivo.
In vitro experiments demonstrate that ASC-derived exosomes (ASC-Exos) significantly promoted the proliferation and migration of both cells more effectively than ASC-derived ectosomes (ASC-Ectos). Furthermore, ASC-Exos facilitated a stronger differentiation of BMSCs into chondrogenic cells than ASC-Ectos, but both inhibited chondrocyte apoptosis to a similar extent. In the osteochondral defect model of rats, ASC-Exos promoted cartilage regeneration in situ better than ASC-Ectos. At 8 weeks, the hydrogel containing exosomes group (Gel + Exo group) had higher macroscopic and histological scores, a higher value of trabecular bone volume fraction (BV/TV), a lower value of trabecular thickness (Tb.Sp), and a better remodeling of extracellular matrix than the hydrogel containing ectosomes group (Gel + Ecto group). At 4 and 8 weeks, the expression of CD206 and Arginase-1 in the Gel + Exo group was significantly higher than that in the Gel + Ecto group.
Our findings indicate that administering ASC-Exos may be a more effective EV strategy for cartilage regeneration than the administration of ASC-Ectos.
Rheumatoid arthritis (RA) is a common autoimmune disease leading to pain, disability, and even death. Although studies have revealed that aberrant activation of STING was implicated in various ...autoimmune diseases, the role of STING in RA remains unclear. In the current study, we demonstrated that STING activation was pivotal in RA pathogenesis. As the accumulation of dsDNA, a specific stimulus for STING, is a feature of RA, we developed a spherical polyethyleneimine-coated mesoporous polydopamine nanoparticles loaded with STING antagonist C-176 (PEI-PDA@C-176 NPs) for treating RA. The fabricated NPs with biocompatibility had high DNA adsorption ability and could effectively inhibit the STING pathway and inflammation in macrophages. Intra-articular administration of PEI-PDA@C-176 NPs could effectively reduce joint damage in mice models of dsDNA-induced arthritis and collagen-induced arthritis by inhibiting STING pathway. We concluded that materials with synergistic effects of STING inhibition might be an efficacious strategy to treat RA.
Schematic illustration of (A) the Chemical Composition of PEI-PDA@C-176 NPs and (B) the mechanism utilized for therapeutic of RA via inhibiting the STING pathway. Display omitted
•We demonstrated significant accumulation of cell-free double stranded DNA (dsDNA) and STING activation played a pivotal role in Rheumatoid arthritis (RA) pathogenesis.•We synthesized a spherical polyethyleneimine coated mesoporous polydopamine nanoparticles loaded with STING antagonist C-176 (PEI-PDA@C-176 NPs).•The obtained PDA NPs adsorb dsDNA and release C-176, thus inhibit STING signaling simultaneously.•The obtained PDA NPs effectively reduce synovium and cartilage damage in both dsDNA-induced arthritis model and collagen induced arthritis model via synergetic STING inhibition.
Osteoarthritis (OA) is a leading cause of physical disability among aging populations, with no available drugs able to efficiently restore the balance between cartilage matrix synthesis and ...degradation. Also, OA has not been accurately classified into subpopulations, hindering the development toward personalized precision medicine.
In the present study, we identified a subpopulation of OA patients displaying high activation level of epidermal growth factor receptor (EGFR). With Col2a1-creERT2; Egfrf/f mice, it was found that the activation of EGFR, indicated by EGFR phosphorylation (pEGFR), led to the destruction of joints. Excitingly, EGFR inhibition prohibited cartilage matrix degeneration and promoted cartilage regeneration. The Food and Drug Administration (FDA)-approved drug gefitinib could efficiently inhibit EGFR functions in OA joints and restore cartilage structure and function in the mouse model as well as the clinical case report.
Overall, our findings suggested the concept of the EGFR activated OA subpopulation and illustrated the mechanism of EGFR signaling in regulating cartilage homeostasis. Gefitinib could be a promising disease-modifying drug for this OA subpopulation treatment.
•There is a subpopulation of osteoarthritic patients with high activation level of EGFR (pEGFRhigh).•Gefitinib can simultaneously promote ECM synthesis and inhibit further degradation in pEGFRhigh osteoarthritic cartilage.•Intra-articular controlled-release of gefitinib could be a therapeutic strategy for pEGFRhigh OA treatment.•EGFR activation regulates OA development through inhibition of autophagy.
Osteoarthritis (OA) is one of the most prevalent musculoskeletal disorder worldwide, but most treatments in clinics are designed as a “one-size-fits-all-approach”. We found that not all OA patients are the same, and specifically in this case, there is a group of people with high activation level of EGFR, a functional protein in the cells of cartilage. The anti-cancer drug gefitinib was discovered to have multiple functions in protecting articular cartilage from destruction in EGFR activated OA. Our research therefore highlighted the OA subpopulation concept and suggested a novel OA therapeutic strategy.
Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, ...nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the N-terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.
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•We synthesized a self-adaptive pyroptosis-responsive nanoliposome system.•The pyroptotic protein integrates with the cardiolipin of liposomes and forms pores.•The liposomes release anti-pyroptotic drugs in a pyroptosis-responsive manner.•The liposomes significantly inhibit pyroptosis in autoimmune inflammatory diseases.
The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic ...joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4
T cells in peripheral blood and spleen. Deletion of CD4
T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4
T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint-liver axis mediated by matrikine-activated CD4
T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease. Intra-articular bleeding induces cartilage degradation through down-reulation of cartilage Akt pathway. During this process, the soluble COL II released from the damaged cartilage can activate peripheral CD4
T cells, differention into Th17 cells and secretion of IL-17, which consequently induces liver impairment. Intra-articular application of sc79 (inhibitor of Akt pathway) can prevent the cartilage damage as well as its peripheral influences.
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