OA Model Research Articles

Cepharanthine Ameliorates Chondrocytic Inflammation and Osteoarthritis via Regulating the MAPK/NF-κB-Autophagy Pathway.

Osteoarthritis is a worldwide joint disease caused by abnormal chondrocytic metabolism. However, traditional therapeutic methods aimed at anti-inflammation for early-stage disease are palliative. In the present study, we demonstrated that cepharanthine (CEP), extracted from the plant Stephania cepharantha, exerted protective medicinal efficacy on osteoarthritis for the first time. In our in vitro study, CEP suppressed the elevated expression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and inducible nitric oxide synthase (iNOS) stimulated by IL-1β or TNF-α by inhibiting the activation of MAPK and NF-κB signaling pathways, and upregulated the protein expression of aggrecan, collagen II, and Sox9. Also, CEP could reverse the reduced level of cellular autophagy in IL-1β or TNF-α–induced chondrocytes, indicating that the protective effect of CEP on osteoarthritis was achieved by restoring MAPK/NF-κB-mediated autophagy. Furthermore, in a murine OA model, CEP mitigated cartilage degradation and prevented osteoarthritis in the CEP-treated groups versus the OA group. Hence, our results revealed the therapeutic prospect of CEP for anti-osteoarthritic treatment.

SEMA6D, Negatively Regulated by miR-7, Contributes to C28/I2 chondrocyte's Catabolic and Anabolic Activities via p38 Signaling Pathway.

MiR-7 has been recognized as an osteoarthritis (OA-)-promoting factor, but the specific downstream pathway of miR-7 still remains unknown. Further investigation of the molecular regulatory mechanism of miR-7 might help develop a novel therapeutic method for OA. In this study, we revealed that Semaphorin 6D (SEMA6D) was a direct target gene of miR-7 and presented a negative regulatory relation with SEMA6D in vitro and in vivo. SEMA6D could improve OA in rat OA models, as indicated by H&E and Safranin O-Fast green staining, and also μCT analysis. Further evaluation of SEMA6D suggested that SEMA6D promotes the anabolism and reduces the catabolism of C28/I2 chondrocytes via inhibiting the activation of the p38 pathway. The present research illustrated that SEMA6D is a negatively regulatory factor of miR-7 and a pivotal mediator of catabolism and anabolism in C28/I2 chondrocytes. SEMA6D exerts its function via inhibiting the activation of the p38 pathway.

Asiaticoside ameliorates osteoarthritis progression through activation of Nrf2/HO-1 and inhibition of the NF-κB pathway

Osteoarthritis has become the fourth cause of disability in the world and its occurrence and development are caused by apoptosis and extracellular matrix (ECM) degradation of chondrocytes. Asiaticoside (ASI) is a triterpene saponin compound obtained from Centella Asiatica and has anti-inflammatory and anti-apoptotic effects in various diseases. However, its effects on OA are not clear. In this study, we reported that ASI has a protective effect on the occurrence and progression of OA in vivo and in vitro, and demonstrated its potential molecular mechanism. In vitro, ASI treatment inhibited the release of pro-apoptotic factors induced by TBHP and promoted the release of the anti-apoptotic proteins. In addition, ASI promotes the expression of Aggrecan and Collagen II, while inhibiting the expression of thrombospondin motifs 5 (ADAMTS5) and matrix metalloproteinase-13 (MMP-13), which causes extracellular matrix (ECM) degradation. Mechanistically, ASI exerts its anti-apoptotic effect by activating the Nrf2/HO-1 pathway and preventing p65 from binding to DNA. Similarly, in vivo, ASI has been shown to have a protective effect in a mouse OA model. The conclusion is that our research shows that ASI can be used as a potential drug for the treatment of OA.

Protective role of microRNA-23a/b-3p inhibition against osteoarthritis through Gremlin1-depenent activation of TGF-β/smad signaling in chondrocytesa.

The changed biomechanical environment of chondrocytes elicited by altered extracellular matrix is reported to accelerate the progression of OA. MicroRNAs (miRNAs or miRs) have emerged as major regulators in chondrocyte function. Hence, we explored effect of miR-23a/b-3p on OA in regulating chondrocyte growth. The medial meniscus and anterior cruciate ligaments of right knee was removed to induce a mouse model of OA. miR-23a/b-3p and Gremlin1 (Grem1) expressions in OA were determined by RT-qPCR. Dual luciferase reporter gene assay was conducted to assess their relationship in the context of OA. Loss- and gain-of-function assays were adopted to clarify their effects on OA by determining the release of pro-inflammatory proteins and the apoptosis of chondrocytes. RT-qPCR determined increased miR-23a/b-3p expression and decreased Grem1 expression in the setting OA. Inhibiting miR-23a/b-3p or overexpressing Grem1 activated transforming growth factor-β/solvated metal atom dispersed 3 (TGF-β/Smad) signaling to prevent OA development. Silencing Grem1 ablated suppressive effects of miR-23a/b-3p inhibitor on the release of pro-inflammatory proteins and the apoptosis of chondrocytes. To conclude, inhibition of miR-23a/b-3p delays OA progression through Grem1-mediated activation of TGF-β/Smad signaling, contributing to deepen understanding of the pathogenesis of OA.

The protective effect of kirenol in osteoarthritis: an in vitro and in vivo study

BackgroundOsteoarthritis (OA) is a chronic degenerative disease, its main characteristic involves articular cartilage destruction and inflammation response, absent of effective medical treatment. Our current research aimed to explore anti-inflammatory effect of kirenol, a diterpenoid natural product compound, in the development of OA and its potential molecular mechanism through in vitro and in vivo study.MethodsIn vitro, chondrocytes were pretreated with kirenol for 2 h before IL-1β stimulation. Production of NO, PGE2, TNF-α, IL-6, aggrecan, collagen-II, MMP13and ADAMTS5 were evaluated by the Griess reaction and ELISAs. The mRNA (aggrecan and collagen-II) and protein expression (COX-2, iNOS, P65, IκB, PI3K, AKT) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and P65. The in vivo effect of kirenol was evaluated in mice OA models induced by destabilization of the medial meniscus (DMM).ResultsWe found that kirenol inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, ADAMTS-5. Besides, kirenol remarkably decreased IL-1β-induced degradation of aggrecan and collagen-II. Furthermore, kirenol significantly inhibited IL-1β-induced phosphorylation of PI3K/Akt and NF-κB signaling. In vivo, the cartilage in kirenol-treated mice exhibited less cartilage degradation and lower OARSI scores.ConclusionsTaken together, the results of this study provide potent evidence that kirenol could be utilized as a potentially therapeutic agent in prevention and treatment of OA.

CD14 DEFICIENCY REDUCES LEUKOCYTE INFILTRATION AND MODULATES CHEMOKINE EXPRESSION IN THE SYNOVIUM AND FAT PAD AFTER JOINT INJURY IN MICE

Purpose: CD14 is a cell-surface co-receptor that facilitates Toll-like receptor signaling, and deficiency of CD14 protects mice from progression of cartilage degeneration in the destabilization of the medial meniscus (DMM) model of OA. CD14 is highly expressed by myeloid cells, and binding of TLR ligands to the CD14/TLR complex activates inflammatory signaling and promotes chronic inflammation. In this study, we tested whether CD14 deficiency influences development or persistence of synovial/fat pad (SM/FP) inflammation after DMM injury in mice, by assessing infiltrating monocyte, resident macrophage and T-lymphocytes, and SM/FP chemokine expression.

DEVELOPMENT OF AN ANIMAL-PRODUCT-FREE SYNOVIAL BIOCHIP MODEL AS FIRST STEP TOWARDS MULTI-TISSUE CROSSTALK MODELS IN OSTEOARTHRITIS

Purpose: Knee osteoarthritis (kOA) which has long been regarded as a wear and tear disease of articular cartilage is nowadays considered a whole-joint-disease with multifactorial etiology. In the past years, chronic synovitis has been identified to significantly contribute to kOA progression, aggravating detrimental cellular crosstalk between fibroblast-like synoviocytes (FLS) and chondrocytes due to a constant pro-inflammatory and tissue degrading tissue environment. Given the still unmet need for reliable in vitro disease models of OA, this study aims to establish an authentic human 3D biochip model of synovial joint tissue.

Triamcinolone acetonide-loaded nanoparticles encapsulated by CD90+ MCSs-derived microvesicles drive anti-inflammatory properties and promote cartilage regeneration after osteoarthritis

BackgroundOsteoarthritis (OA) is a highly prevalent human degenerative joint disorder that has long plagued patients. Glucocorticoid injection into the intra-articular (IA) cavity provides potential short-term analgesia and anti-inflammatory effects, but long-term IA injections cause loss of cartilage. Synovial mesenchymal stem cells (MSCs) reportedly promote cartilage proliferation and increase cartilage content.MethodsCD90+ MCS-derived micro-vesicle (CD90@MV)-coated nanoparticle (CD90@NP) was developed. CD90+ MCSs were extracted from human synovial tissue. Cytochalasin B (CB) relaxed the interaction between the cytoskeleton and the cell membranes of the CD90+ MCSs, stimulating CD90@MV secretion. Poly (lactic-co-glycolic acid) (PLGA) nanoparticle was coated with CD90@MV, and a model glucocorticoid, triamcinolone acetonide (TA), was encapsulated in the CD90@NP (T-CD90@NP). The chondroprotective effect of T-CD90@NP was validated in rabbit and rat OA models.ResultsThe CD90@MV membrane proteins were similar to that of CD90+ MCSs, indicating that CD90@MV bio-activity was similar to the cartilage proliferation-inducing CD90+ MCSs. CD90@NP binding to injured primary cartilage cells was significantly stronger than to erythrocyte membrane-coated nanoparticles (RNP). In the rabbit OA model, the long-term IA treatment with T-CD90@NP showed significantly enhanced repair of damaged cartilage compared to TA and CD90+ MCS treatments. In the rat OA model, the short-term IA treatment with T-CD90@NP showed effective anti-inflammatory ability similar to that of TA treatment. Moreover, the long-term IA treatment with T-CD90@NP induced cartilage to restart the cell cycle and reduced cartilage apoptosis. T-CD90@NP promoted the regeneration of chondrocytes, reduced apoptosis via the FOXO pathway, and influenced type 2 macrophage polarization to regulate inflammation through IL-10.ConclusionThis study confirmed that T-CD90@NP promoted chondrocyte proliferation and anti-inflammation, improving the effects of a clinical glucocorticoid treatment plan.Graphical

Diamond Open Access in Norway 2017–2020

We see from information published elsewhere that Gold OA is on the increase globally. The OA Diamond study indicates that Diamond OA is an important component of scholarly communications, with an estimated 8–9% of the total global scholarly output. These numbers, however, are on a global scale and are not necessarily representative of any given country; country case studies are needed to find this information. Norway is a country where the government has declared a 100% OA goal and most research has public funding. Norway has good financing structures for various models of OA, and it has a national CRIS system. This study tries to find and present numbers for articles in scholarly journals to describe both recent developments and relative numbers for Norway as a whole, and for scholarly fields in Norway, with regards to Diamond OA. Numbers for and development of Gold OA will also be given and commented upon to some extent.

Development and characterization of a humanized mouse model of osteoarthritis

In light of the role of immune cells in OA pathogenesis, the development of sophisticated animal models closely mimicking the immune dysregulation during the disease development and progression could be instrumental for the preclinical evaluation of novel treatments. Among these models, immunologically humanized mice may represent a relevant system, particularly for testing immune-interacting DMOADs or cell therapies before their transfer to the clinic. Our objective, therefore, was to develop an experimental model of OA by destabilization of the medial meniscus (DMM) in humanized mice. Irradiated 5-week-old NOD/LtSz-scid IL2Rγnull (NSG) mice were humanized by intravenous injection of CD34+ human hematopoietic stem cells. The engraftment efficiency was evaluated by flow cytometry 17 weeks after the humanization procedure. Humanized and non-humanized NSG mice underwent DMM or sham surgery and OA development was assessed 1, 6, and 12 weeks after the surgery. 120 days after the humanization, human T and B lymphocytes, macrophages and NK cells, were present in the blood and spleen of the humanized NSG mice. The DMM surgery induced articular cartilage and meniscal alterations associated with an increase in OA and the meniscal score. Moreover, the surgery triggered an inflammatory response that was sustained at a low grade in the DMM group. Our study shows for the first time the feasibility of inducing OA by DMM in humanized mice. This novel OA model could constitute a useful tool to bridge the gap between the preclinical and clinical evaluation of immune interacting DMOADs and cell-based therapies.

Effect of Dietary Polyphenols on Osteoarthritis-Molecular Mechanisms.

Osteoarthritis is a common crippling and degenerative disease resulting in irreversible functional changes due to damage of the cartilage and other tissues of the joint. With limited safe and effective pharmaceutical treatments, the demand and use for alternative therapeutic approaches with symptomatic relief for OA patients have increased. Clinical, pre-clinical, and in vitro studies have demonstrated that polyphenols can exert pain-relieving symptoms coupled with increased functional capacity in OA models. This review will highlight studies carried out in the last five years to define the efficacies and underlying mechanisms in polyphenols such as quercetin, resveratrol, curcumin, epigallocatechin-3-gallate, rosmarinic acid, genistein, ginger, berries, silver fir, pine bark, and Boswellia. Most of these studies indicate that polyphenols exhibit their beneficial roles through regulating changes at the biochemical and molecular levels, inducing or inhibiting various signaling pathways related to inflammation and oxidative stress. Polyphenols have also been implicated in modulating microRNA at the posttranscriptional level to counteract OA pathogenesis.

Can CD200R1 Agonists Slow the Progression of Osteoarthritis Secondary to Injury?

Post-traumatic knee osteoarthritis is characterized by cartilage degeneration, subchondral bone remodeling, osteophyte formation, and synovial changes. Therapeutic targeting of inflammatory activity in the knee immediately post injury may alter the course of osteoarthritis development. This study aimed to determine whether CD200R1 agonists, namely the protein therapeutic CD200Fc or the synthetic DNA aptamer CCS13, both known to act as anti-inflammatory agents, are able to delay the pathogenesis of injury-associated knee osteoarthritis in a murine model. Ten week old male C57BL/6 mice were randomized and surgical destabilization of the medial meniscus (DMM) to induce knee arthritis or sham surgery as a control were performed. CCS13 was evaluated as a therapeutic treatment along with CD200Fc and a phosphate-buffered saline vehicle control. Oligonucleotides were injected intra-articularly beginning one week after surgery, with a total of six injections administered prior to sacrifice at 12 weeks post-surgery. Histopathological assessment was used as the primary outcome measure to assess cartilage and synovial changes, while µCT imaging was used to compare the changes to the subchondral bone between untreated and treated arthritic groups. We did not find any attenuation of cartilage degeneration or synovitis in DMM mice with CD200Fc or CCS13 at 12 weeks post-surgery, nor stereological differences in the properties of subchondral bone. The use of CD200R1 agonists to blunt the inflammatory response in the knee are insufficient to prevent disease progression in the mouse DMM model of OA without anatomical restoration of the normal joint biomechanics.

Ginsenoside-Rb1 prevents bone cartilage destruction through down-regulation of p-Akt, p-P38, and p-P65 signaling in rabbit

BackgroundOsteoarthritis (OA) is the most common joint complaint resulting in pain, disability, and loss of quality of life. On the other hand, ginsenoside-Rb1 is a plant product derived from ginseng that possesses immune-regulation and anti-inflammatory activities. However, it has been reported that different rout of administration but hydrogel-based Ginsenoside-Rb1 in an OA rabbit model has not been investigated. PurposeThe aim of this study was to investigate the potential effects of ginsenoside-Rb1 such as anti-arthritic activity in a rabbit knee OA model via NF- κB, PI3K/Akt, and P38/(MAPK) pathways. Study DesignIn the current study, rabbit osteoarthritis was induced by hollow trephine on the femur trochlea and the hydrogel-based Ginsenoside-Rb1 sheets were inserted on the rabbit knee to assess the anti-arthritis activity of ginsenoside-Rb1 which is sustained release. MethodsAfter the hydrogel-based Rb1 sheet insert on the rabbit knee, macroscopic and micro CT was performed for investigation of chondroprotective effect. Matrix metalloproteinases (MMPs) and apoptotic expression were assessed through Immunohistochemistry and RT-PCR assay. In addition, the flow cytometry technique was used for the investigation of intracellular reactive oxygen species (ROS) production and histological changes were examined by HE, safranin O, and Masson trichrome staining method. Furthermore, the NF- κB, PI3K/Akt, and P38/(MAPK) pathways were investigated using Western blot analysis. ResultsMacroscopic and micro CT investigation of hydrogel-Rb1 treatment showed a dose-dependent chondroprotective effect. Immunohistochemistry and RT-PCR revealed that expression of matrix metalloproteinases (MMPs) and apoptotic markers TNF-α, caspase-3, and bax are down-regulated in a dose-dependent fashion following implantation of hydrogel-Rb. Higher levels of intracellular reactive oxygen species (ROS) were observed in the OA group. In histopathological investigation of hydrogel-Rb1 exhibited larger amounts of chondro cells, glycosaminoglycan's, and collagen compared to the defect group. Furthermore, the NF- κB, PI3K/Akt, and P38/(MAPK) pathways were downregulated by hydrogel-Rb1 while the disease model showed upstream. In the meantime, MMP expression level was considerably down-regulated. ConclusionsOur results indicate the protective effect of ginsenoside-Rb1 against OA pathogenesis through prevention of apoptosis with suppression of ROS production and activation of NF-κB signaling through downregulation of the MAPK and PI3K/Akt signaling pathways.

Similarities and differences between rat and mouse chondrocyte gene expression induced by IL-1\u03b2

BackgroundOsteoarthritis (OA) is the most prevalent degenerative joint disease. In vitro experiments are an intuitive method used to investigate its early pathogenesis. Chondrocyte inflammation models in rats and mice are often used as in vitro models of OA. However, similarities and differences between them in the early stages of inflammation have not been reported.ObjectiveThis paper seeks to compare the chondrocyte phenotype of rats and mice in the early inflammatory state and identify chondrocytes suitable for the study of early OA.MethodsUnder similar conditions, chondrocytes from rats and mice were stimulated using the same IL-1β concentration for a short period of time. The phenotypic changes of chondrocytes were observed under a microscope. The treated chondrocytes were subjected to RNA-seq to identify similarities and differences in gene expression. Chondrocytes were labelled with EdU for proliferation analysis. Cell proliferation-associated proteins, including minichromosome maintenance 2 (MCM2), minichromosome maintenance 5 (MCM5), Lamin B1, proliferating cell nuclear antigen (PCNA), and Cyclin D1, were analysed by immunocytochemical staining, cell immunofluorescence, and Western blots to verify the RNA-seq results.ResultsRNA-seq revealed that the expression patterns of cytokines, chemokines, matrix metalloproteinases, and collagen were similar between the rat and mouse chondrocyte inflammation models. Nonetheless, the expression of proliferation-related genes showed the opposite pattern. The RNA-seq results were further verified by subsequent experiments. The expression levels of MCM2, MCM5, Lamin B1, PCNA, and Cyclin D1 were significantly upregulated in rat chondrocytes (P < 0.05) and mouse chondrocytes (P < 0.05).ConclusionsBased on the findings, the rat chondrocyte inflammation model may help in the study of the early pathological mechanism of OA.

Ononin ameliorates inflammation and cartilage degradation in rat chondrocytes with IL-1\u03b2-induced osteoarthritis by downregulating the MAPK and NF-\u03baB pathways

BackgroundOsteoarthritis (OA) treatment aims to improve inflammation and delay cartilage degeneration. However, there is no effective strategy presently available. Ononin, a representative isoflavone glycoside component extracted from natural Chinese herbs, exerts anti-inflammatory and proliferative effects. However, the therapeutic effect of ononin on chondrocyte inflammation remains unclear.MethodsIn this study, we explored the therapeutic effect and potential mechanism of ononin in OA by establishing an interleukin-1 beta (IL-1β)-induced chondrocyte inflammation model.ResultsOur results verified that ononin alleviated the IL-1β-induced decrease in chondrocyte viability, attenuated the overexpression of the inflammatory factors tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6), and simultaneously inhibited the expression of cartilage extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteinase-13 (MMP-13). Furthermore, the decomposition of Collagen II protein could be alleviated in the OA model by ononin. Finally, ononin improved chondrocyte inflammation by downregulating the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signalling pathways.ConclusionOur findings suggested that ononin could inhibit the IL-1β-induced proinflammatory response and ECM degradation in chondrocytes by interfering with the abnormal activation of the MAPK and NF-κB pathways, indicating its protective effect against OA.

Downregulation of miR-3680–3p inhibits the progression of osteoarthritis via targeting OGG1

BackgroundOsteoarthritis (OA) is a degenerative joint disease that seriously endangers the health of middle-aged and elderly people. MicroRNA (miRNA) regulation is associated with several diseases, including OA. This study aimed to explore the role and mechanism of miR-3680–3p in regulating OA progression. MethodsGSE105027 and GSE143514 were downloaded from Gene Expression Omnibus (GEO) and differentially expressed miRNAs between control and OA-affected cartilage were obtained by R software. GSE55235 gene expression profile was downloaded and analyzed the differentially expressed genes. In vitro study, chondrocyte was administrated by interleukin-1β (IL-1β) to mimic an in vitro model of OA. The apoptotic and cell cycle arrest were assessed by flowcytometry. IL-6 and TNF-α expressions were measured by the enzyme-linked immunosorbant assay (ELISA). Moreover, the OA rat model was established to explore the function of miR-3680–3p/OGG1 axis in vivo. ResultsGSE105027 identified 266 differentially expressed miRNAs and GSE143514 identified 160 differentially expressed miRNAs. MiR-3680–3p was significantly upregulated in OA samples in comparison to normal cartilage samples. IL-1β significantly reduced the cell viability than control chondrocytes, this effect was reversed by miR-3680–3p antagomir. Treatment with miR-3680–3p antagomir could partially reversed the IL-1β-induced promotion of apoptosis of chondrocytes. IL-1β increased the expression of MMP1 and MMP13, while the expression of matrix related protein, such as aggrecan, was significantly downregulated in IL-1β-treated chondrocytic cells. Inhibition of miR-3680–3p expression by an antagomir could reverse this phenotype. OGG1 was predicted and verified as a direct target of miR-3680–3p. Moreover, our in vivo study found that after knockdown of miR-3680–3p alleviated the development of OA in rat models. ConclusionInhibition of miR-3680–3p reversed the IL-1β induced chondrocytes injury and delayed the progression of OA via targeting OGG1.

Engineered adipose-derived stem cells with IGF-1-modified mRNA ameliorates osteoarthritis development

BackgroundOsteoarthritis (OA), a prevalent degenerative disease characterized by degradation of extracellular matrix (ECM), still lacks effective disease-modifying therapy. Mesenchymal stem cells (MSCs) transplantation has been regarded as the most promising approach for OA treatment while engrafting cells alone might not be adequate for effective regeneration. Genetic modification has been used to optimize MSC-based therapy; however, there are still significant limitations that prevent the clinical translation of this therapy including low efficacy and safety concerns. Recently, chemically modified mRNA (modRNA) represents a promising alternative for the gene-enhanced MSC therapy. In this regard, we hypothesized that adipose derived stem cells (ADSCs) engineered with modRNA encoding insulin-like growth factor 1 (IGF-1) were superior to native ADSCs on ameliorating OA development.MethodsMouse ADSCs were acquired from adipose tissue and transfected with modRNAs. First, the kinetics and efficacy of modRNA-mediated gene transfer in mouse ADSCs were analyzed in vitro. Next, we applied an indirect co-culture system to analyze the pro-anabolic potential of IGF-1 modRNA engineered ADSCs (named as IGF-1-ADSCs) on chondrocytes. Finally, we evaluated the cell retention and chondroprotective effect of IGF-1-ADSCs in vivo using fluorescent labeling, histology and immunohistochemistry.ResultsmodRNA transfected mouse ADSCs with high efficiency (85 ± 5%) and the IGF-1 modRNA-transfected ADSCs facilitated burst-like production of bio-functional IGF-1 protein. In vitro, IGF-1-ADSCs induced increased anabolic markers expression of chondrocytes in inflammation environment compared to untreated ADSCs. In a murine OA model, histological and immunohistochemical analysis of knee joints harvested at 4 weeks and 8 weeks after OA induction suggested IGF-1-ADSCs had superior therapeutic effect over native ADSCs demonstrated by lower histological OARSI score and decreased loss of cartilage ECM.ConclusionsThese findings collectively supported the therapeutic potential of IGF-1-ADSCs for clinical OA management and cartilage repair.

The ROS‐responsive scavenger with intrinsic antioxidant capability and enhanced immunomodulatory effects for cartilage protection and osteoarthritis remission

Oxidative stress has close relationship with the progression of osteoarthritis and thus is an important therapeutic target. The use of antioxidants alone has common disadvantages such as low bioavailability, poor stability, and rapid joint clearance or toxicity at high concentrations. To achieve both reactive oxygen species (ROS) responsive scavenging ability and drug targeted delivery ability, a novel polymer (PEG-PTK-PEG) was synthesized through a simple and direct reaction between polythioketal (PTK) and m-PEG-acrylate. In addition to excellent mechanical properties and high drug loading capacity, the degradation products of PEG-PTK-PEG responding to the ROS accumulating microenvironment also have excellent biocompatibility and extremely low toxicity. Further, the PEG-PTK-PEG nanoparticles (NPs) loaded with astaxanthin (ASTA), which is an antioxidant with high biological safety, could effectively reduce ROS expression and release ASTA slowly and accurately in the area of high ROS expression as a result of the polymer degradation. In the OA model, the PEG-PTK-PEG@ASTA could effectively inhibit the expression of ROS, thereby downregulating the MAPK signaling pathway and inducing the conversion of macrophages from the M1 phenotype to the M2 phenotype. The synergistic effect of PEG-PTK-PEG's ROS-responsive drug delivery ability and ROS scavenging ability significantly promoted the therapeutic effect of OA, providing a new and effective strategy for the clinical treatment of OA.

Chondroprotective effects of multiple PRP injections in osteoarthritis by apoptosis regulation and increased aggrecan synthesis- Immunohistochemistry based Guinea pig study

ObjectiveUse of Immunohistochemistry as a tool to assess anti-apoptotic effects and cartilage regeneration effects of PRP in guinea pig model of spontaneous OA. Study designControlled Laboratory Study involving Dunkin-Hartley guinea pigs. Methods12 Dunkin-Hartley guinea pigs (weighing ∼600–800 g) were chosen for this study. One knee of each animal received 3 injections of allogenic PRP at weekly intervals (Group A = 12 Knees). The other knee received normal saline and acted as the control group (Group B = 12 Knees). Half of the animals from each group (subgroups A3 & B3 = 6 Knees each) were sacrificed at 3 months, and the remaining half (subgroups A6 & B6 = 6 Knees each) were sacrificed at 6 months after intervention. Immunohistochemistry (IHC) staining and evaluation were done for Collagen-II, Caspase-3 and Aggrecan. ResultsThe mean IHC score for Caspase-3 were significantly low in PRP knees compared to placebo Knees at 3 months (P = 0.031) and 6 months (P = 0.012) suggesting its down-regulation and inhibition of apoptosis. The mean IHC score for content of collagen- II and aggrecan at 3 months were higher in PRP Knees (A3) compared to placebo (B3) (Not significant). At 6 months, the Mean IHC Score decreased in both PRP (A6) and Control Knees (B6) for Collagen, but increased for aggrecan compared to its value at 3 months; and this was better in PRP group than in the control (P = 0.024). ConclusionMultiple injections of PRP has a chondroprotective role by its anti-apoptotic effect and by increasing the aggrecan content in ECM.

Meta-analysis Integrated With Multi-omics Data Analysis to Elucidate Pathogenic Mechanisms of Age-Related Knee Osteoarthritis in Mice.

Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the majority of clinically presenting KOA, the bulk of our mechanistic understanding of KOA has been derived using surgically induced posttraumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics data analysis to elucidate pathogenic mechanisms of age-related KOA in mice. Protein-level data were integrated with transcriptomic profiling to reveal inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of cartilage aging were unique from those observed following PTOA, with less than 3% overlap between the 2 models. At the nexus of the 3 aging hallmarks, advanced glycation end product (AGE)/receptor for AGE (RAGE) emerged as the most statistically robust pathway associated with age-related KOA. This pathway was further supported by analysis of mass spectrometry data. Notably, the change in AGE-RAGE signaling over time was exclusively observed in male mice, suggesting sexual dimorphism in the pathogenesis of age-induced KOA in murine models. Collectively, these findings implicate dysregulation of AGE-RAGE signaling as a sex-dependent driver of age-related KOA.