Cytohesin-2/ARNO: A Novel Bridge Between Cell Migration and Immunoregulation in Synovial Fibroblasts

The guanine nucleotide exchange factor cytohesin-2 (ARNO) is a major activator of the small GTPase ARF6 that has been shown to play an important role(s) in cell adhesion, migration and cytoskeleton reorganization in various cell types and models of disease. Interestingly, dysregulated cell migration, in tandem with hyper-inflammatory responses, is one of the hallmarks associated with activated synovial fibroblasts (SFs) during chronic inflammatory joint diseases, like rheumatoid arthritis. The role of ARNO in this process has previously been unexplored but we hypothesized that the pro-inflammatory milieu of inflamed joints locally induces activation of ARNO-mediated pathways in SFs, promoting an invasive cell phenotype that ultimately leads to bone and cartilage damage. Thus, we used small interference RNA to investigate the impact of ARNO on the pathological migration and inflammatory responses of murine SFs, revealing a fully functional ARNO-ARF6 pathway which can be rapidly activated by IL-1β. Such signalling promotes cell migration and formation of focal adhesions. Unexpectedly, ARNO was also shown to modulate SF-inflammatory responses, dictating their precise cytokine and chemokine expression profile. Our results uncover a novel role for ARNO in SF-dependent inflammation, that potentially links pathogenic migration with initiation of local joint inflammation, offering new approaches for targeting the fibroblast compartment in chronic arthritis and joint disease.

Efficient Treatment of Rheumatoid Arthritis by Degradable LPCE Nano-Conjugate-Delivered p65 siRNA

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide, causing severe cartilage damage and disability. Despite the recent progress made in RA treatment, limitations remain in achieving early and efficient therapeutic intervention. Advanced therapeutic strategies are in high demand, and siRNA-based therapeutic technology with a gene-silencing ability represents a new approach for RA treatment. In this study, we created a cationic delivery micelle consisting of low-molecular-weight (LMW) polyethylenimine (PEI)–cholesterol–polyethylene glycol (PEG) (LPCE) for small interfering RNA (siRNA)-based RA gene therapy. The carrier is based on LMW PEI and modified with cholesterol and PEG. With these two modifications, the LPCE micelle becomes multifunctional, and it efficiently delivered siRNA to macrophages with a high efficiency greater than 70%. The synthesized LPCE exhibits strong siRNA protection ability and high safety. By delivering nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 siRNA, the p65 siRNA/LPCE complex efficiently inhibited macrophage-based cytokine release in vitro. Local administration of the p65 siRNA/LPCE complex exhibited a fast and potent anti-inflammatory effect against RA in a mouse model. According to the results of this study, the functionalized LPCE micelle that we prepared has potential gene therapeutic implications for RA.

LncRNAs and Rheumatoid Arthritis: From Identifying Mechanisms to Clinical Investigation

Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix destruction caused by immune system abnormalities are the main features of RA. The use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) has achieved great advances in the therapy of RA. Yet there are still patients facing the problem of poor response to drug therapy or drug intolerance. Current therapy methods can only moderate RA progress, but cannot stop or reverse the damage it has caused. Recent studies have reported that there are a variety of long non-coding RNAs (LncRNAs) that have been implicated in mediating many aspects of RA. Understanding the mechanism of LncRNAs in RA is therefore critical for the development of new therapy strategies and prevention strategies. In this review, we systematically elucidate the biological roles and mechanisms of action of LncRNAs and their mechanisms of action in RA. Additionally, we also highlight the potential value of LncRNAs in the clinical diagnosis and therapy of RA.

Application of Embedded Smart Wearable Device Monitoring in Joint Cartilage Injury and Rehabilitation Training

Joint injuries cause varying degrees of damage to joint cartilage. The purpose of this paper is to study the application of embedded smart wearable device monitoring in articular cartilage injury and rehabilitation training. This paper studies what an embedded system is and what a smart wearable device is and also introduces the rehabilitation training method of articular cartilage injury. We cited an embedded matching cost algorithm and an improved AD-Census. The joint cartilage damage and rehabilitation training are monitored. Finally, we introduced the types of smart wearable devices and different types of application fields. The results of this paper show that, after an articular cartilage injury, the joint function significantly recovers using the staged exercise rehabilitation training based on embedded smart wearable device monitoring. We concluded that, from 2013 to 2020, smart wearable devices are very promising in the medical field. In 2020, the value will reach 20 million US dollars.

Hypoxia-inducible Factor Expression Is Related to Apoptosis and Cartilage Degradation in Temporomandibular Joint Osteoarthritis

Background: It remains unclear whether hypoxic conditions affect apoptosis and contribute to degradation of cartilaginous tissues in osteoarthritis (OA) lesions. In this study, we hypothesized that hypoxic conditions induced the accumulation of hypoxia-inducible factor (HIF) and activated apoptosis to contribute to OA cartilage degeneration in vivo.Methods: Malocclusion stress was applied for 2 weeks, 4 weeks and 8 weeks to induce an OA-like lesion animal model (OD) in rats. Histological analysis was performed by H&E staining and safranin O/fast green staining. The expression levels of protein in condylar cartilage were examined by immunostaining to evaluate cartilage degeneration.Results: We found apparent histological phenotypes associated with degeneration in the occlusion disorder stress (OD) group. The OD group at 4 weeks and 8 weeks had obviously reduced expression of Acan and Col II in cartilage. In contrast, the OD groups had higher levels of Col X, ADAMTS5 and MMP13 in the condylar cartilage than the control group. Moreover, the OD group cartilage had prominent degenerative changes with reduced levels of HIF1α and increased levels of HIF2α and the apoptosis factor Caspase3 in condylar cartilage at 8 weeks.Occlusion disorder stress results in cartilage degeneration. HIF1α and HIF2α are involved in temporomandibular joint (TMJ) cartilage homeostasis by regulating chondrocyte apoptosis, which contributes to TMJ cartilage degeneration. Conclusion: Thus, abnormal hypoxic conditions inducing opposite expression patterns of HIF1α and HIF2α could be involved in the pathogenesis of condylar cartilage degeneration. HIF2α may provide a potential negative feedback mechanism for HIF1α during cartilage damage.

HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis

Background The aim of this study was to evaluate whether histone deacetylase 4 S246/467/632A mutant (m-HDAC4) has enhanced function at histone deacetylase 4 (HDAC4) to attenuate cartilage degeneration in a rat model of osteoarthritis (OA). Methods Chondrocytes were infected with Ad-m-HDAC4-GFP or Ad-HDAC4-GFP for 24 h, incubated with interleukin-1β (IL-1β 10 ng/mL) for 24 h, and then measured by RT-qPCR. Male Sprague-Dawley rats (n = 48) were randomly divided into four groups and transduced with different vectors: ACLT/Ad-GFP, ACLT/Ad-HDAC4-GFP, ACLT/Ad-m-HDAC4-GFP, and sham/Ad-GFP. All rats received intra-articular injections 48 h after the operation and every 3 weeks thereafter. Cartilage damage was assessed using radiography and Safranin O staining and quantified using the OARSI score. The hypertrophic and anabolic molecules were detected by immunohistochemistry and RT-qPCR. Results M-HDAC4 decreased the expression levels of Runx-2, Mmp-13, and Col 10a1, but increased the levels of Col 2a1 and ACAN more effectively than HDAC4 in the IL-1β-induced chondrocyte OA model; upregulation of HDAC4 and m-HDAC4 in the rat OA model suppressed Runx-2 and MMP-13 production, and enhanced Col 2a1 and ACAN synthesis. Stronger Safranin O staining was detected in rats treated with m-HDAC4 than in those treated with HDAC4. The resulting OARSI scores were lower in the Ad-m-HDAC4 group (5.80 ± 0.45) than in the Ad-HDAC4 group (9.67 ± 1.83, P = 0.045). The OARSI scores were highest in rat knees that underwent ACLT treated with Ad-GFP control adenovirus vector (14.93 ± 2.14, P = 0.019 compared with Ad-HDAC4 group; P = 0.003 compared with Ad-m-HDAC4 group). Lower Runx-2 and MMP-13 production, and stronger Col 2a1 and ACAN synthesis were detected in rats treated with m-HDAC4 than in those treated with HDAC4. Conclusions M-HDAC4 repressed chondrocyte hypertrophy and induced chondrocyte anabolism in the nucleus. M-HDAC4 was more effective in attenuating articular cartilage damage than HDAC4.

Hubungan Rasionalitas Penggunaan Obat Nyeri Terhadap Tingkat Nyeri Pada Lansia Dengan Osteoarthritis Di Panti Pelayanan Sosial Lanjut Usia Bisma Upakara Pemalang Tahun 2021

Osteoarthritis is a degenerative joint disease characterized by cartilage damage and often occurs in the elderly. Diseases that are often found in the community. Management of osteoarthritis is aimed at controlling or relieving pain. Inappropriate drug selection can cause the drug to be ineffective, exacerbate a disease, and cause unwanted effects. This study aims to determine the relationship between the rationality of the use of pain medication on the level of pain in the elderly with osteoarthritis. The research design is a descriptive correlative study with a cross sectional approach. The sampling technique used was total sampling with a total of 43 respondents. Data collection tools using a questionnaire and statistical tests using the Kolmogorov Smirnov test. The results of the study found that the percentage related to rationality of rational pain medication (69.8%) was irrational (30.2%) and at the level of pain experienced mild pain (18.6%), moderate pain (67.4%), and moderate pain. weight (14.0%). Statistical test results obtained p value of 0.042 (<0.05) Ho is rejected, which means that there is a significant relationship between the rationality of pain medication use and pain levels in the elderly with osteoarthritis at the Bisma Upakara Elderly Social Service Institution, Pemalang. . The results of this study recommend for health workers to provide or improve health education related to the rationality of using pain medication.Keywords: Pain, Osteoarthritis, Rationality AbstrakOsteoarthritis adalah penyakit radang sendi degeneratif dengan di tandai dengan adanya kerusakan kartilago dan sering terjadi pada lansia .Penyakit yang sering dijumpai pada masyarakat. Penatalaksanaan osteoarthritis ditujukan pada pengendalian atau menghilangkan nyeri. Pemilihan obat yang tidak tepat dapat menyebabkan obat menjadi tidak berkhasiat, memperparah suatu penyakit, dan menimbulkan efek yang tidak diinginkan.Penelitian ini bertujuan untuk mengetahui hubungan rasionalitas penggunaan obat nyeri terhadap tingkat nyeri pada lansia dengan osteoarthritis. Desain penelitian studi deskriptif korelatif dengan pendekatancross sectional. Teknik pengambilan sampel menggunakan total samplingdengan jumlah 43 responden. Alat pengumpulan data menggunakan kuesioner dan uji statistik menggunakan uji Kolmogorov Smirnov. Hasil dari penelitiandidapatkan persentase terkait rasionalitas obat nyeri yang rasional (69,8%) tidak rasional (30,2%) dan pada tingkat nyeri yang mengalami nyeri ringan (18,6%), nyeri sedang (67,4%), dan nyeri berat (14,0%).hasil uji statistik didapatkan p value sebesar 0,042 (< 0,05) yang berarti ada hubungan yang signifikan rasionalitas penggunaan obat nyeri terhadap tingkat nyeri pada lansia dengan osteoarthritis di Panti Pelayanan Sosial Lanjut Usia Bisma Upakara Pemalang. Hasil peneltian ini merekomendasikan bagi tenaga kesehatan untuk memberikan atau meningkatkan pendidikan kesehatan terkait dengan rasionalitas penggunaan obat nyeri. Kata kunci : Nyeri; Osteoarthritis; Rasionalitas

Salvianolic Acid B Activates Chondrocytes Autophagy and Reduces Chondrocyte Apoptosis in Obese Mice via the KCNQ1OT1/Mir-128-3p/SIRT1 Signaling Pathways

Purpose: Salvianolic acid B (Sal B) possesses strong anti-inflammatory and antioxidant activity. This study aims to explore the underlying mechanism of Sal B to improve the obesity-related osteoarthritis (OA). Methods: C57BL/6J male mice were fed with a standard diet, a high fat diet (HFD), or HFD with Sal B (25 mg/kg), and mouse body weights and osteoarticular inflammatory factor levels were examined. Mouse chondrogenic cell line ATDC5 were transfected with lncRNA KCNQ1 overlapping transcript 1 small hairpin RNA (KCNQ1OT1 shRNA), miR-128-3p mimic or Sirtuin-1 small interfering RNA (SIRT1 siRNA), then stimulated with Palmitic acid (PA) followed by the treatment of Sal B. Then, inflammatory response, apoptosis, and autophagy of ATDC5 cells in different groups were detected. Results: Sal B reduced body weight, decreased the levels of inflammatory markers, and improved cartilage damage in OA mice. KCNQ1OT1 was downregulated in OA mice and PA- stimulated ATDC5 cells. Sal B protected ATDC5 cells against PA-mediated inflammation, apoptosis, and the inhibition of autophagy, while knockdown of KCNQ1OT1 reversed these results. KCNQ1OT1 was found to be functioned as a ceRNA to bind and downregulate the expression of miR-128-3p that was upregulated in PA-induced cells. Furthermore, SIRT1 was verified as a target of miR-128-3p. MiR-128-3p overexpression reversed the effects of Sal B on inflammatory response, apoptosis, and autophagy in PA-stimulated cells, and knockdown of SIRT1 displayed similar results. Conclusion: Sal B exerted a chondroprotective effect by upregulating KCNQ1OT1, which indicates Sal B can used for a therapeutic agent in obesity-related OA.

Biocompatible Hydrogel for Intra-Articular Implantation Comprising Cationic and Anionic Polymers of Natural Origin: In Vivo Evaluation in a Rabbit Model

We describe the functional capability of a cross-linked hydrogel composed of sulfated glycosaminoglycans and a cationic cellulose by conducting trials on experimental animal models using intra-articular implants to treat an articular disease called osteoarthritis. Forty-eight mature New Zealand white rabbits were divided into three experimental groups: A, B, and C. Group A and B underwent unilateral anterior cruciate ligament transection (ACLT) of the right knee. Subsequently, both knees of group A were treated with the injectable formulation under study. Meanwhile, group B was treated with sterile PBS (placebo). The animals of group C were surgically operated in both knees: Commercial hyaluronic acid (HA) was implanted in the left knee, and the formulation under study was implanted in the right knee. After implantation, all specimens underwent several evaluations at 3, 6, and 12 months postoperatively. At 6 months, no significant differences were detected between the right and left knees of the different groups. However, significant differences were observed between both knees at 12 months in group C, with less cartilage damage in the right knees implanted with our hydrogel. Therefore, in vivo studies have demonstrated hydrogel safety, superior permanence, and less cartilage damage for long-term follow up 12 months after implantation for the formulation under study compared with commercial HA.

LncRNA Malat-1 From MSCs-Derived Extracellular Vesicles Suppresses Inflammation and Cartilage Degradation in Osteoarthritis

Purpose: Extracellular Vesicles (EVs) derived from hMSCs, have the potential to alleviate cartilage damage and inflammation. We aimed to explore the effects of EVs derived from lncRNA malat‐1-overexpressing human mesenchymal stem cells (hMSCs) on chondrocytes.Material and Methods: hMSCs-derived Extracellular Vesicles (hMSCs-EVs) were identified by transmission electron microscopy and western blot. We used a Sprague-Dawley (SD) rat model of CollagenaseⅡ-induced osteoarthritis (OA) as well as IL-1β-induced OA chondrocytes. Lentiviral vectors were used to overexpress lncRNA malat‐1 in hMSCs. Chondrocyte proliferation, inflammation, extracellular matrix degradation, and cell migration were measured by Edu staining, ELISA, western blot analysis, and transwell assay. Chondrocyte apoptosis was evaluated by flow cytometry, Hoechst 33342/PI Staining, and western blot. Safranine O-fast green (S-O) staining and HE staining were used to assess morphologic alterations of the rat knee joint.Results: hMSCsmalat−1-EVs decreased MMP-13, IL-6, and Caspase-3 expression in IL-1β-induced OA chondrocytes. Moreover, hMSCsmalat−1-EVs promoted chondrocyte proliferation and migration, suppressed apoptosis, and attenuated IL-1β-induced chondrocyte injury. Our animal experiments suggested that hMSCsmalat−1-EVs were sufficient to prevent cartilage degeneration.Conclusion: Our findings show that lncRNA malat-1from hMSCs‐delivered EVs can promote chondrocyte proliferation, alleviate chondrocyte inflammation and cartilage degeneration, and enhance chondrocyte repair. Overall, hMSCsmalat−1-EVs might be a new potential therapeutic option for patients with OA.