Prevent Cartilage Degradation Research Articles

Microneedle-Delivered PDA@Exo for Multifaceted Osteoarthritis Treatment via PI3K-Akt-mTOR Pathway.

Osteoarthritis (OA) is marked by cartilage deterioration, subchondral bone changes, and an inflammatory microenvironment. The study introduces the Microneedle-Delivered Polydopamine-Exosome (PDA@Exo MN), a therapeutic that not only preserves cartilage and promotes bone regeneration but also improves localized drug delivery through enhanced penetration capabilities. PDA@Exo MN shows strong reactive oxygen species(ROS) scavenging abilities and high biocompatibility, fostering osteogenesis and balancing anabolic and catabolic processes in cartilage. It directs macrophage polarization from M0 to the anti-inflammatory M2 phenotype. RNA sequencing of treated chondrocytes demonstrates restored cellular function and activated antioxidant responses, with modulated inflammatory pathways. The PI3K-AKT-mTOR pathway's activation, essential for PDA@Exo's effects, is confirmed via bioinformatics and Western blot. In vivo assessments robustly validate that PDA@Exo MN prevents cartilage degradation and OA progression, supported by histological assessments and micro-CT analysis, highlighting its disease-modifying impact. The excellent biocompatibility of PDA@Exo MN, verified through histological (H&E) and blood tests showing no organ damage, underscores its safety and efficacy for OA therapy, making it a novel and multifunctional nanomedical approach in orthopedics, characterized by organ-friendliness and biosecurity.

A Novel Role for Protein Tyrosine Phosphatase 1B in Alleviating Chondrocyte Senescence.

Osteoarthritis (OA) is a kind of arthritis that impairs movement and causes joint discomfort. Recent research has demonstrated a connection between cellular senescence and the degenerative processes of OA chondrocytes. In yeast and human cells, protein tyrosine phosphatase 1B (PTP1B) knockdown prolongs longevity; however, the function of PTP1B in chondrocyte senescence has not been investigated. The goal of the current investigation was to evaluate PTP1B's contribution to human OA chondrocyte senescence. The function of PTP1B and cellular senescence in the onset of OA was investigated and confirmed by using a combination of bioinformatics techniques, clinical samples, and in vitro experimental procedures. The RNA sequencing data pertinent to the OA were obtained using the Gene Expression Omnibus database. Function enrichment analysis, protein-protein correlation analysis, the construction of the correlation regulatory network, and an investigation into possible connections between PTP1B and cellular senescence in OA were all carried out using various bioinformatic techniques. Compared with healthy cartilage, PTP1B expression was increased in OA cartilage. According to a Pearson correlation study, cellular senescence-related genes, including MAP2K1 and ABL1, were highly correlated with PTP1B expression levels in senescent chondrocytes. Furthermore, in vitro tests confirmed that PTP1B knockdown slowed cartilage degradation and prevented chondrocyte senescence in OA. In conclusion, we showed that PTP1B knockdown prevented the senescence of chondrocytes and prevented cartilage degradation in OA. These findings offer a fresh perspective on the pathophysiology of OA, opening up new avenues for OA clinical diagnosis and targeted treatment.

In vitro and in vivo studies of the therapeutic potential of Tinospora crispa extracts in osteoarthritis: Targeting oxidation, inflammation, and chondroprotection

Ethnopharmacological relevanceThe increasing incidence of osteoarthritis (OA), especially among the elderly population, highlights the need for more efficacious treatments that go beyond mere symptomatic relief. Tinospora crispa (L.) Hook. f. & Thomson (TC) boasts a rich traditional heritage, widespread use in Ayurveda, traditional Chinese medicine (TCM), and diverse indigenous healing practices throughout Southeast Asia for treating arthritis, rheumatism, fever, and inflammation. Aim of the studyThis study investigates the anti-inflammatory and chondroprotective potential of TC stem extracts, including ethanolic TC extract (ETCE) and aqueous TC extract (ATCE), in modulating OA pathogenesis through in vitro and in vivo approaches. Materials and methodsThe study utilized LC-MS/MS to identify key compounds in TC stem extracts. In vitro experiments assessed the antioxidative and anti-inflammatory properties of ETCE and ATCE in activated macrophages, while an in vivo monoiodoacetate (MIA)-induced OA rat model evaluated the efficacy of ETCE treatment. Key markers of oxidative stress, such as superoxide dismutase (SOD) and catalase (CAT), were assessed alongside pro-inflammatory cytokines TNF-α and IL-1β, and matrix-degrading enzymes, matrix metalloproteinase (MMP 13 and MMP 3), to evaluate the therapeutic effects of TC stem extracts on OA. ResultsChemical profiling of the extracts was conducted using LC-MS/MS in positive ionization, identifying seven compounds, including pseudolaric acid B, stylopine, and reticuline, which were reported for the first time in this species. The study utilized varying concentrations of TC stem extracts, specifically 6.25–25 μg/mL for in vitro assays and 500 mg/kg for in vivo studies. Our findings also revealed that both ETCE and ATCE exhibit dose-dependent reduction in reactive oxygen species (41%–52%) and nitric oxide (NO) levels (50% and 72%), with ETCE displaying superior antioxidative efficacy and marked anti-inflammatory properties, significantly reducing TNF-α and IL-6 at concentrations above 12.5 μg/mL. In the MIA-induced OA rat model, ETCE treatment notably outperformed ATCE, markedly lowering TNF-α (1.91 ± 0.37 pg/mL) and IL-1β (26.30 ± 3.68 pg/mL) levels and effectively inhibiting MMP 13 and MMP 3 enzymes. Furthermore, macroscopic and histopathological assessments, including ICRS scoring and OARSI grading, indicate that TC stem extracts reduce articular damage and proteoglycan loss in rat knee cartilage. These results suggest that TC stem extracts may play a role in preventing cartilage degradation and potentially alleviating inflammation and pain associated with OA, though further studies are needed to confirm these effects. ConclusionThis study highlights the potential of TC stem extracts as a novel, chondroprotective therapeutic avenue for OA management. By targeting oxidative stress, pro-inflammatory cytokines, and cartilage-degrading enzymes, TC stem extracts promise to prevent cartilage degradation and alleviate inflammation and pain associated with OA.

Progress in the treatment of Osteoarthritis with avocado-soybean unsaponifiable.

Osteoarthritis (OA) is one of the leading causes of joint dysfunction and disability in the elderly, posing serious social problems and a huge socio-economic burden. Existing pharmacological treatments have significant drawbacks, and searching for an effective pharmacological intervention is an urgent priority. Recent studies have demonstrated the chondroprotective, anabolic, and anti-catabolic properties of avocado-soybean unsaponifiable (ASU), a natural plant extract made from avocado and soybean oils, consisting of the remainder of the saponified portion of the product that cannot be made into soap. The main components of ASU are phytosterols, beta-sitosterol, canola stanols, and soya stanols, which are rapidly incorporated into cells. Studies have confirmed the anti-inflammatory, antioxidant, and analgesic properties of phytosterols. ASU slows down the progression of OA primarily by inhibiting pathways involved in the development of OA disease. ASU prevents cartilage degradation by inhibiting the release and activity of matrix metalloproteinases and by increasing the tissue inhibition of these catabolic enzymes; ASU is also involved in the inhibition of the activation of nuclear factor κB (NF-κB) which is a transcriptional inhibitor that regulates the inflammatory response of chondrocytes. NF-κB is a transcription factor that regulates the inflammatory response of chondrocytes, and inhibition of the transfer of the transcription factor NF-κB from the cytoplasm to the nucleus regulates the transcription of many pro-inflammatory factors. By appealing to the mechanism of action and thus achieving anti-inflammatory, anti-catabolic, and pro-synthetic effects on cartilage tissues, AUS is clinically responsive to the reduction of acute pain and OA symptom progression. This paper aims to summarize the studies on the use of avocado-soybean unsaponifiable in the pharmacological treatment of osteoarticular.

Single Cell Profiling Reveals Unique Contributions of Senescent Macrophages across Musculoskeletal Tissues in Posttraumatic Osteoarthritis

Injury to the acute cruciate ligament (ACL) disrupts musculoskeletal tissue architecture and function, leading to atrophy and weakness associated with the development of posttraumatic osteoarthritis (PTOA). The objective of this study was to profile senescent cell burden across skeletal muscle and knee joint capsule compartments and to ascertain the effectiveness of senolytic treatment in mitigation of PTOA. Given the unique features of these tissues, we hypothesized that composition and physiological consequence of senescent cell burden would differ among muscle and joint capsule, and senolytic treatment would prevent cartilage degradation and improve muscle function. We employed a surgical ACL transection model (ACLT) and performed scRNAseq analysis on the quadriceps and joint capsule 14-days post-injury and discerned senescent status by SPiDER-βGal. We also examined the influence of senescent cells on neighboring populations in vitro. We investigated whether senolytic treatment (dasatinib and quercetin; D+Q) improves muscle and joint health 28-d post-injury. scRNAseq revealed that macrophages (MΦ) accounted for 83% of senescent cells in the quadriceps and 48% in the joint capsule. Senescent MΦ exhibited an alternatively activated phenotype (M2) . Gene ontology enrichment analysis in the quadriceps showed downregulation of positive regulation of muscle cell differentiation, and upregulation of secretory granule lumen; in the joint capsule, it revealed upregulation of glycosaminoglycan catabolic process and regulation of ossification. In vitro, we found that mesenchymal progenitors incubated with senescent MΦ conditioned media exhibited upregulation of senescence associated secretory phenotype (SASP) genes and extracellular matrix organization-related genes ( i.e.Col1a1 and Lox). We found upregulation of protein glycosylation and downregulation of chondroitin sulfate proteoglycan biosynthetic process pathways. PTOA mice exhibited significant reductions in quadriceps myofiber cross-sectional area, increased accumulation of M2-like Cd163+ MΦ, and increased fibrosis, which were blunted in D+Q-treated mice. D+Q-treated PTOA mice exhibited a trend of improved peak torque compared to vehicle-treated PTOA mice. Histochemical assessment of whole knee joints revealed compromised articular cartilage and moderate to severe PTOA in vehicle-treated mice, which was blunted in D+Q-treated mice. These findings reveal distinct transcriptional profiles of senescent macrophages isolated from unique musculoskeletal tissues, providing critical insight into the heterogeneity of senescent cell programming following traumatic injury. Further, we show that accumulation of senescent alternatively-activated MΦ likely contributes to musculoskeletal dysfunction and development of PTOA, and that senolytics may improve functional recovery. AR072061. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Importance of Hyaluronic Acid in Biological Systems

Hyaluronic acid (HA) is a crucial component of the extracellular matrix, found abundantly in connective tissues, skin, and synovial fluid. Its unique properties, including hydration capacity and viscoelasticity, play pivotal roles in tissue hydration, lubrication, and wound healing. Despite its ubiquitous presence, the specific mechanisms underlying its diverse biological functions remain the subject of ongoing research. Studies have elucidated HA's involvement in various physiological processes, such as cell proliferation, migration, and differentiation. Its interaction with cell surface receptors modulates signaling pathways implicated in tissue repair and inflammation regulation. Moreover, HA's rheological properties contribute to joint lubrication, facilitating smooth movement and preventing cartilage degradation. Understanding the multifaceted roles of HA holds significant implications for biomedical applications. Its therapeutic potential spans from skincare formulations to regenerative medicine and drug delivery systems. Targeting HA metabolism presents novel strategies for treating conditions like osteoarthritis, dry eye syndrome, and dermal aging. Continued exploration of HA biology promises exciting avenues for scientific advancement and clinical innovation. Emerging technologies, such as biomaterial engineering and nanomedicine, offer opportunities to tailor HA-based interventions for enhanced efficacy and targeted delivery. Additionally, investigating HA's interplay with the immune system could uncover new immunomodulatory therapies. In conclusion, the importance of hyaluronic acid in biological systems is indisputable, given its indispensable roles in tissue homeostasis and repair. By deciphering its intricate mechanisms of action, researchers pave the way for groundbreaking advancements in medicine and biotechnology. Harnessing the therapeutic potential of HA stands poised to revolutionize healthcare, offering solutions to a myriad of pathological conditions and enhancing quality of life.

Inhibition of HOXD11 promotes cartilage degradation and induces osteoarthritis development

The 5′-HOXD genes are important for chondrogenesis in vertebrates, but their roles in osteoarthritis (OA) are still ambiguous. In our study, 5′-HOXD genes involvement contributing to cartilage degradation and OA was investigated. In bioinformatics analysis of 5′-HOXD genes, we obtained the GSE169077 data set related to OA in the GEO and analyzed DEGs using the GEO2R tool attached to the GEO. Then, we screened the mRNA levels of 5′-HOXD genes by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR). We discovered that OA chondrocyte proliferation was inhibited, and apoptosis was increased. Moreover, it was discovered that SOX9 and COL2A1 were downregulated at mRNA and protein levels, while matrix metalloproteinases (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTSs) were upregulated. According to the results of differentially expressed genes (DEGs) and qRT-PCR, we evaluated the protein level of HOXD11 and found that the expression of HOXD11 was downregulated, reversed to MMPs and ADAMTSs but consistent with the cartilage-specific factors, SOX9 and COL2A1. In the lentivirus transfection experiments, HOXD11 overexpression reversed the effects in OA chondrocytes. In human OA articular cartilage, aberrant subchondral bone was formed in hematoxylin–eosin (H&E) and Safranin O and fast green (SOFG) staining results. Furthermore, according to immunohistochemistry findings, SOX9 and HOXD11 expression was inhibited. The results of this study established that HOXD11 was downregulated in OA cartilage and that overexpression of HOXD11 could prevent cartilage degradation in OA.

Duhuo Jisheng Decoction regulates intracellular zinc homeostasis by enhancing autophagy via PTEN/Akt/mTOR pathway to improve knee cartilage degeneration.

Articular cartilage and cartilage matrix degradation are key pathological changes occurring in the early stage of knee osteoarthritis (KOA). However, currently, there are limited strategies for early prevention and treatment of KOA. Duhuo Jisheng Decoction (DHJSD) is a formula quoted in Bei Ji Qian jin Yao Fang, which was compiled by Sun Simiao in the Tang Dynasty of China. As a complementary therapy, it is widely used to treat early-stage KOA in China; however, its mechanism has not been completely elucidated. This study investigated the potential role of DHJSD in preventing cartilage degradation and the underlying mechanism. A rat model of KOA model was established via the Hulth method. Subsequently, 25 rats were randomized into sham (saline), model control (saline), high-DHJSD (1.9g/mL of DHJSD), medium-DHJSD (1.2g/mL of DHJSD), and low-DHJSD groups (0.6g/mL of DHJSD). After 4 weeks of treatment, all rats were sacrificed and the severity of the cartilage degeneration was evaluated by a series of histological methods. The autophagosome was observed using transmission electron microscopy, and the related functional proteins were detected by the western blotting and real-time polymerase chain reaction. Next, the mechanism by which DHJSD improves knee cartilage degeneration was further clarified the in vitro by gene silencing technology combined with a series of functional experiments. The proteins levels of PTEN, Akt, p-Akt, mTOR, and p-mTOR, as well as the marker proteins of autophagy and apoptosis were determined. Zinc levels in chondrocytes were determined using inductively coupled plasma mass spectrometry. Histopathological staining revealed that DHJSD had a protective effect on the cartilage. DHJSD increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in chondrocytes. Moreover, it reduced the phosphorylation levels of Akt and mTOR and the levels of zinc, MMP-13, Bax, and Bcl-2. Following PTEN silencing, this DHJSD-mediated reduction in Akt and mTOR phosphorylation and Bax, Bcl-2, and zinc levels were further decreased; in addition, DHJSD-mediated increase in LC3 and Beclin-1 levels was decreased. DHJSD inhibits the Akt/mTOR signaling pathway by targeting PTEN to promote autophagy in chondrocytes, which may help reduce MMP-13 production by regulating zinc levels in chondrocytes.

Human placental extract: a potential therapeutic in treating osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease marked by cartilage degradation and loss of function. Recently, there have been increased efforts to attenuate and reverse OA by stimulating cartilage regeneration and preventing cartilage degradation. Human placental extract (HPE) may be an option due to its anti-inflammatory, antioxidant, and growth stimulatory properties. These properties are useful in preventing cell death and senescence, which may optimize in-situ cartilage regeneration. In this review, we discuss the anatomy and physiology of the placenta, as well as explore in vivo and in vitro studies assessing its effects on tissue regeneration. Finally, we assess the potential role of HPE in cartilage regenerative medicine and OA. The Medline database was utilized for all studies that involved the use of HPE or human placenta hydrolysate. Exclusion criteria included articles not written in English, conference reviews, editorials, letters to the editor, surveys, case reports, and case series. HPE had significant anti-inflammatory and regenerative properties in vitro and in vivo. Furthermore, HPE had a role in attenuating cellular senescence and cell apoptosis via reduction of reactive oxidative species both in vitro and in vivo. One study explored the effects of HPE in OA and demonstrated reduction in cartilage catabolic gene expression, indicating HPE's effect in attenuating OA. HPE houses favorable properties that can attenuate and reverse tissue damage. This may be a beneficial therapeutic in OA as it creates a more favorable environment for in-situ cartilage regeneration. More well designed in-vitro and in-vivo studies are needed to define the role of HPE in treating OA.

Stevioside protects primary articular chondrocytes against IL-1β-induced inflammation and catabolism by targeting integrin.

Osteoarthritis (OA) is a common, progressive, and chronic disorder of the joints that is characterized by the inflammation and degradation of articular cartilage and is known to significantly impair quality of daily life. Stevioside (SVS) is a natural diterpenoid glycoside that has anti-inflammatory benefits. Hence, in the current research, it was hypothesized that SVS might exert anti-inflammatory effects on articular chondrocytes and alleviate cartilage degradation in mice with OA. The expression of inflammatory cytokines, like inducible nitric oxide synthase (iNOS), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and cyclooxygenase-2 (COX-2) in chondrocytes after interleukin-1β (IL-1β) exposure, was inhibited by the pretreatment of SVS. As well, SVS inhibited the reduction of collagen II and sry-box transcription factor 9 (SOX9) in chondrocytes stimulated by IL-1β and suppressed the expression of MMP3 and MMP13. Further, after treatment with SVS, cell cytometry, autophagy flux, and related protein expression showed diminished cell apoptosis and reduced autophagy impairment. Moreover, SVS blocked the activation of phosphoinositide-3-kinase/Akt/nuclear factor-kappa beta (PI3K/Akt/NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways stimulated by IL-1β. This resulted in decreased cellular inflammation. In vivo experiments with intra-articular injections of SVS in mice with the DMM mouse model demonstrated a decrease in cartilage degradation and an improvement in subchondral bone remodeling. After the integrin αVβ3-related knockdown using siRNA, a reversed effect was observed on the anti-inflammatory, anabolic promoting, catabolic blocking, and NF-κB and MAPK signaling pathway inhibition of SVS on chondrocytes treated with IL-1β. The above findings highlighted that SVS blocked IL-1β, triggered an inflammatory response in mice chondrocytes, and prevented cartilage degradation in vivo through integrin αVβ3. This suggested that SVS might serve as a novel therapeutic option for OA.

Functional Mechanism of Mesenchymal Stem Cell-Derived Exosomes in Articular Cartilage Regeneration

As the aging of the population, a chronic degenerative joint disease - Osteoarthritis (OA), its incidence and severity are increasing. Compared with cells, the immunogenicity of the exon is low and the immunomodulatory performance is excellent. Various types of mesenchymal stem cell-derived exosomes (MSC-EXOs) are now being used to treat cartilage injury and disease as target drugs or delivery vehicles. A thorough examination of the existing evidence is required in light of the emerging evidence on the effective mechanism and method of MSC-EXOs in OA. This article reviews the specific mechanism and latest research progress of MSCs derived exosomes in OA treatment. It mainly summarizes three mechanisms of action of exosomes: a. Enhancing extracellular matrix (ECM) and preventing cartilage degradation; b. Promoting chondrocyte migration, proliferation, migration, and inhibiting chondrocyte apoptosis, c. Influencing immune protection or immune destruction signals. In addition, the difficulties of exosomes in the clinical treatment of OA are briefly reviewed, with the hope of providing ideas for developing biomaterials scaffolds and clinical treatment of MSC-EXOs.

Touchable Electrochemical Hydrogel Sensor for Detection of Reactive Oxygen Species‐induced Cellular Senescence in Articular Chondrocytes

AbstractIn this study, a reactive oxygen species (ROS)‐responsive hydrogel sensor (PD/MnO2 hydrogel) is developed that can efficiently detect senescent cells. Using immature murine articular chondrocytes with serial passages, the sensor can identify small interfering RNA (siRNA) knockdown of peroxisome proliferator‐activated receptor‐alpha (PPARα) based on the concentration of ROS in cells, simultaneously maintaining its balance via scavenging activity to prevent cartilage degradation in osteoarthritis (OA). The hydrogel sensor exhibits a change in electronic properties, with a distinct resistance from 201.9 kΩ for P0 to 362.9 kΩ for P3, and fluorescence off/on performance with an increase in passaging time. In vitro investigation using PPARα‐specific siRNA reveals a correlation between pressure sensitivity and senescent activity, wherein an elevation in observed signal occurred (41.5%). In vivo analysis reveals significant decrease in degradation of the cartilage of both young, 3 months old aged, 18 months old, and PPARα−/− mice compared to PPARα+/+ mice based on safranin O stains. The expression level of interleukin‐1β is reduced in the cartilage of aged PPARα−/− mice after implantation with hydrogel, indicating the potential of PD/MnO2 hydrogel as a therapeutic modality against OA.

Adhesive ginsenoside compound K patches for cartilage tissue regeneration.

Biomaterial-based drug delivery systems have been developed to expedite cartilage regeneration; however, challenges related to drug recovery, validation, and efficient drug delivery remain. For instance, compound K (CK) is a major metabolite of ginsenosides that is known to protect against joint degeneration by inhibiting the production of inflammatory cytokines and the activation of immune cells. However, its effects on cartilage degradation and tissue regeneration remain unclear. Additionally, tissue-adhesive drug delivery depots that stably adhere to cartilage defects are required for CK delivery. In this study, CK-loaded adhesive patches were reported to seal cartilage defects and deliver CK to defect sites, preventing cartilage degradation and accelerating cartilage tissue regeneration. Adhesive patches are stable and suitable for application in surgical procedures under physiological conditions and show excellent adhesiveness to cartilage surfaces. In addition, there were no significant differences in the adhesive polymeric networks before and after CK loading. CK-loaded hydrocaffeic acid-conjugated chitosan patches significantly inhibited the stimulation of cartilage-degrading enzymes and apoptosis in osteoarthritic cartilage by releasing CK in cartilage defects. Additionally, the NFkB signaling pathway of released CK from the adhesive patches in the treatment of osteoarthritis is revealed. Thus, the CK-loaded adhesive patches are expected to significantly contribute to cartilage regeneration.

Upregulated FOXM1 stimulates chondrocyte senescence in Acot12-/-Nudt7-/- double knockout mice.

Rationale: One of the hallmarks of osteoarthritis (OA), the most common degenerative joint disease, is increased numbers of senescent chondrocytes. Targeting senescent chondrocytes or signaling mechanisms leading to senescence could be a promising new therapeutic approach for OA treatment. However, understanding the key targets and links between chondrocyte senescence and OA remains unclear. Methods: Senescent chondrocytes were identified from Nudt7-/-, Acot12-/-, double-knockout mice lacking Acot12 and Nudt7 (dKO) and applied to microarray. The presence of forkhead transcription factor M1 (FOXM1) was detected in aged, dKO, and destabilization of the medial meniscus (DMM) cartilages and articular chondrocytes, and the effect of FoxM1 overexpression and acetyl-CoA treatment on cartilage homeostasis was examined using immunohistochemistry, quantitative real-time PCR (qRT-PCR), cell apoptosis and proliferation assay, and safranin O staining. Delivery of Rho@PAA-MnO2 (MnO2 nanosheet) or heparin-ACBP/COS-GA-siFoxM1 (ACBP-siFoxM1) nanoparticles into DMM cartilage was performed. Results: Here, we propose the specific capture of acetyl-CoA with the delivery of (FoxM1 siRNA (siFoxM1) to prevent cartilage degradation by inhibiting the axis of chondrocyte senescence. dKO stimulate chondrocyte senescence via the upregulation of FoxM1 and contribute to severe cartilage breakdown. We found that the accumulation of acetyl-CoA in the dKO mice may be responsible for the upregulation of FoxM1 during OA pathogenesis. Moreover, scavenging reactive oxygen species (ROS) induced by chondrocyte senescence via the implantation of MnO2 nanosheets or delivery of siFoxM1 functionalized with acetyl-CoA binding protein (ACBP) to capture acetyl-CoA using an injectable bioactive nanoparticle (siFoxM1-ACBP-NP) significantly suppressed DMM-induced cartilage destruction. Conclusion: We found that the loss of Acot12 and Nudt7 stimulates chondrocyte senescence via the upregulation of FoxM1 and accumulation of acetyl-CoA, and the application of siFoxM1-ACBP-NP is a potential therapeutic strategy for OA treatment.

In vitro analysis of the effects of plant-derived chondroitin sulfate from intestinal barrier to chondrocytes

• Greendroitine® is a new plant-derived chondroitin sulfate with low molecular weight. • Greendroitine® is able to cross the intestinal barrier. • Greendroitine® is able to exert beneficial effects on chondrocytes in vitro also in OA condition. • Greendroitine® is a promising new nutraceutical candidate to the oral intake in human. Chondroitin is well known to regulate several biological functions and to exert a critical role in the regulation of joint physiology maintaining proper chondrocyte activity. The aim of this study was to explore the ability of a new chondroitin, from plant origin, to induce different biological effects analyzing the link between certain chemical properties and the specific biological significance. Its biological effects were analyzed by intestinal permeability and in vitro osteoarthritis conditions verifing data to other chondroitin forms from animal and non-animal sources. Plant-derived chondroitin shows a heterogeneous chemical-biological profile, which may be responsible for many specific functions observed in vitro . Furthermore, it exhibits a better absorption profile without affecting the intestinal barrier and modulates disintegrin and metalloproteinase with thrombospondin 5 motifs to prevent cartilage degradation. Plant-derived chondroitin, Greendroitin®, can be considered an excellent new strategy to improve cartilage trophism, based on surprising biological properties in osteoarthritis in vitro model.

Glutamine metabolism modulates chondrocyte inflammatory response.

Osteoarthritis is the most common joint disease in the world with significant societal consequences but lacks effective disease-modifying interventions. The pathophysiology consists of a prominent inflammatory component that can be targeted to prevent cartilage degradation and structural defects. Intracellular metabolism has emerged as a culprit of the inflammatory response in chondrocytes, with both processes co-regulating each other. The role of glutamine metabolism in chondrocytes, especially in the context of inflammation, lacks a thorough understanding and is the focus of this work. We display that mouse chondrocytes utilize glutamine for energy production and anabolic processes. Furthermore, we show that glutamine deprivation itself causes metabolic reprogramming and decreases the inflammatory response of chondrocytes through inhibition of NF-κB activity. Finally, we display that glutamine deprivation promotes autophagy and that ammonia is an inhibitor of autophagy. Overall, we identify a relationship between glutamine metabolism and inflammatory signaling and display the need for increased study of chondrocyte metabolic systems.

Poster 206: TIPE2 Mitigates the Histopathology of Osteoarthritis in An Accelerate Aging Mouse Model

Poster 206: TIPE2 Mitigates the Histopathology of Osteoarthritis in An Accelerate Aging Mouse Model

Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1.

Post-traumatic OA (PTOA) is often triggered by injurious, high-impact loading events which result in rapid, excessive chondrocyte cell death and a phenotypic shift in residual cells toward a more catabolic state. As such, the identification of a disease-modifying OA drug (DMOAD) that can protect chondrocytes from death following impact injury, and thereby prevent cartilage degradation and progression to PTOA, would offer a novel intervention. We have previously shown that urocortin-1 (Ucn) is an essential endogenous pro-survival factor that protects chondrocytes from OA-associated pro-apoptotic stimuli. Here, using a drop tower PTOA-induction model, we demonstrate the extent of Ucn’s chondroprotective role in cartilage explants exposed to excessive impact load. Using pathway-specific agonists and antagonists, we show that Ucn acts to block load-induced intracellular calcium accumulation through blockade of the non-selective cation channel Piezo1 rather than TRPV4. This protective effect is mediated primarily through the Ucn receptor CRF-R1 rather than CRF-R2. Crucially, we demonstrate that the chondroprotective effect of Ucn is maintained whether it is applied pre-impact or post-impact, highlighting the potential of Ucn as a novel DMOAD for the prevention of injurious impact overload-induced PTOA.

Chondrocyte-specific genomic editing enabled by hybrid exosomes for osteoarthritis treatment.

Rationale: A cell-specific delivery vehicle is required to achieve gene editing of the disease-associated cells, so the hereditable genome editing reactions are confined within these cells without affecting healthy cells. A hybrid exosome-based nano-sized delivery vehicle derived by fusion of engineered exosomes and liposomes will be able to encapsulate and deliver CRISPR/Cas9 plasmids selectively to chondrocytes embedded in articular cartilage and attenuate the condition of cartilage damage.Methods: Chondrocyte-targeting exosomes (CAP-Exo) were constructed by genetically fusing a chondrocyte affinity peptide (CAP) at the N-terminus of the exosomal surface protein Lamp2b. Membrane fusion of the CAP-Exo with liposomes formed hybrid CAP-exosomes (hybrid CAP-Exo) which were used to encapsulate CRISPR/Cas9 plasmids. By intra-articular (IA) administration, hybrid CAP-Exo/Cas9 sgMMP-13 entered the chondrocytes of rats with cartilage damages that mimicked the condition of osteoarthritis.Results: The hybrid CAP-Exo entered the deep region of the cartilage matrix in arthritic rats on IA administration, delivered the plasmid Cas9 sgMMP-13 to chondrocytes, knocked down the matrix metalloproteinase 13 (MMP-13), efficiently ablated the expression of MMP-13 in chondrocytes, and attenuated the hydrolytic degradation of the extracellular matrix proteins in the cartilage.Conclusion: Chondrocyte-specific knockdown of MMP-13 mitigates or prevents cartilage degradation in arthritic rats, showing that hybrid CAP-Exo/Cas9 sgMMP-13 may alleviate osteoarthritis.

Abrine promotes cell proliferation and inhibits apoptosis of interleukin-1β-stimulated chondrocytes via PIM2/VEGF signalling in osteoarthritis

BackgroundOsteoarthritis (OA), a common joint disorder with an increasing incidence worldwide, severely affects the quality of life of patients. In Chinese herbal medicine, Abrus cantoniensis Hance is considered to exert protective effects on the liver and to have beneficial effects on the gallbladder; additionally, it has antibacterial and anti-inflammatory properties, as well as the ability to enhance immunity, scavenge free radicals, regulate smooth muscle function, and improve endurance. Abrine extracted from A. cantoniensis Hance has been reported as a main functional compound capable of treating chronic inflammation. PurposeIn this study, we explored the effect of abrine on OA progression. Study DesignBioinformatics analysis was performed on abrine and its potential targets in OA, using the Comparative Toxicogenomics Database, GSE1919 dataset from the Gene Expression Omnibus database, Gene Set Enrichment Analysis, and docking interaction analysis. MethodsThe effect of abrine in vitro was analysed by Cell Counting Kit 8 assays, colony formation assays, enzyme-linked immunosorbent assay, flow cytometry analysis, quantitative real-time PCR, and western blotting using human transformed chondrocyte cell line C28/I2. The effect of abrine was evaluated in vivo using the anterior cruciate ligament transection (ACLT) Sprague-Dawley rat OA model. ResultsAbrine enhanced the proliferation of interleukin (IL)-1β-stimulated C28/I2 cells in a dose-dependant manner. Expression of pro-inflammatory cytokines was induced by IL-1β treatment, whereas abrine treatment repressed the induction of C28/I2 cells in a dose dependant manner (p < 0.05). Abrine induced cell proliferation and inhibited apoptosis in IL-1β-stimulated C28/I2 cells (p < 0.05). Abrine also inhibited Proviral Integrations of Moloney virus 2 (PIM2) expression in IL-1β-stimulated C28/I2 cells (p < 0.05). The expression of vascular endothelial growth factor (VEGF), p-VEGFR2, and p-eNOS was induced by IL-1β treatment in C28/I2 cells, while abrine inhibited this induction in a dose dependant manner. Treatment with abrine decreased the expression levels of PIM2 and VEGF in IL-1β-stimulated C28/I2 cells (p < 0.05). Overexpression of PIM2 induced cell proliferation and inhibited apoptosis in IL-1β-stimulated C28/I2 cells, while VEGF silencing reversed this effect (p < 0.05). Finally, abrine prevented cartilage degradation in the ACLT model. ConclusionWe demonstrated that abrine promoted cell proliferation and inhibited apoptosis in IL-1β-stimulated C28/I2 cells through PIM2/VEGF signalling. These findings indicate PIM2 to be a potential drug target. Moreover, abrine has potential applicability as a therapeutic agent against OA.