Cartilage Degeneration In Osteoarthritis Research Articles

Mechanism of Delaying Cartilage Degeneration in Knee Osteoarthritis with Rongjin Niantong Recipe Based on lncRNA NEAT1 and Nrf2/ARE Pathway

<bold>Objective</bold> To evaluate the effect of Rongjin Niantong Recipe on knee osteoarthritis model rats, and to explore the mechanism of delaying cartilage degeneration in knee osteoarthritis based on long noncoding RNA (lncRNA) NEAT1 and Nrf2/ARE pathway. <bold>Methods</bold> After adaptive feeding for one week, a total of 45 SPF SD rats aged two months were randomly divided into blank group and sodium iodoacetate group, with 15,30 cases in each group. Under anesthesia, 0.05 mL sodium iodoacetate at a concentration of 20 mg/mL was injected into the right knee joint to establish the knee osteoarthritis model, and the blank group was injected with the same amount of normal saline. After modeling was assessed to be successful, the sodium iodoacetate group were randomly divided into model group and Rongjin Niantong Recipe group, with 15 cases in each group. The Rongjin Niantong Recipe group were given 1.9 g/(kg·d) the medicine by gavage, and the blank group and the model group were given the same amount of normal saline by gavage for eight weeks. After the intervention, all groups were sacrificed under anesthesia, and the right knee tissues were separated and collected; HE staining was used to observe the pathological changes; Western blot was used to detect the expression levels of Nrf2, heme oxygenase-1 (HO-1), NAD (P) H quinone oxidoreductase-1 (NQO-1), kelch like ECH-associated protein 1 (Keap1) and inducible nitric oxide synthase (iNOS) in cartilage; Real-time PCR was used to detect the expression of lncRNA NEAT1 in cartilage tissue. <bold>Results</bold> 1) Pathological changes of cartilage tissue: the cartilage matrix was light red and uniform, with complete tissue structure and clear tissue margins of each layer in the blank group; in the model group, the chondrocytes grew in clusters with thinner tangent layer. The surface layer was destroyed and the transitional layer and the radiation layer became disordered and partial calcified. There were obvious calcifications in the calcified layer. In addition, the adhesion line between the calcified layer and the subchondral bone fluctuated greatly and was discontinuous. The tangents of the superficial layer in the Rongjin Niantong Recipe group were completed and basically paralleled to the articular surface, and the transitional layer, radiation layer, calcification layer and other layers were relatively clear. 2) Expressions of Nrf2/ARE pathway related proteins in the cartilage: compared with the blank group, the protein expression levels of Keap1 and iNOS of the model group significantly increased (<italic>P</italic>&lt;0.05) and the protein expression levels of Nrf2, HO-1 and NQO-1 significantly decreased (<italic>P</italic>&lt;0.05). Compared with the model group, the protein expression levels of Keap1 and iNOS in the Rongjin Niantong Recipe group significantly decreased (<italic>P</italic>&lt;0.05), while the protein expression levels of Nrf2, HO-1 and NQO-1 significantly increased (<italic>P</italic>&lt;0.05). 3) Expressions of lncRNA NEAT1 in cartilage: compared with the blank group, the expression level of lncRNA NEAT1 in the model group was significantly higher (<italic>P</italic>&lt;0.05); compared with the model group, the expression level of lncRNA NEAT1 in the Rongjin Niantong Recipe group significantly decreased (<italic>P</italic>&lt;0.05). <bold>Conclusion</bold> Rongjin Niantong Recipe can delay cartilage degeneration in rats with osteoarthritis. The mechanism may be related to the down-regulation of lncRNA NEAT1 level, up-regulation of Nrf2 signal and antioxidant signal molecules expressions, and down-regulation of pro-oxidation signal molecules and inhibition of oxidative stress level.

A Progress Report and Roadmap for Microphysiological Systems and Organ-On-A-Chip Technologies to Be More Predictive Models in Human (Knee) Osteoarthritis.

Osteoarthritis (OA), a chronic debilitating joint disease affecting hundreds of million people globally, is associated with significant pain and socioeconomic costs. Current treatment modalities are palliative and unable to stop the progressive degeneration of articular cartilage in OA. Scientific attention has shifted from the historical view of OA as a wear-and-tear cartilage disorder to its recognition as a whole-joint disease, highlighting the contribution of other knee joint tissues in OA pathogenesis. Despite much progress in the field of microfluidic systems/organs-on-a-chip in other research fields, current in vitro models in use do not yet accurately reflect the complexity of the OA pathophenotype. In this review, we provide: 1) a detailed overview of the most significant recent developments in the field of microsystems approaches for OA modeling, and 2) an OA-pathophysiology-based bioengineering roadmap for the requirements of the next generation of more predictive and authentic microscale systems fit for the purpose of not only disease modeling but also of drug screening to potentially allow OA animal model reduction and replacement in the near future.

Impaired glucose metabolism underlies articular cartilage degeneration in osteoarthritis.

Osteoarthritis (OA) is the leading joint disease characterized by cartilage destruction and loss of mobility. Accumulating evidence indicates that the incidence and severity of OA increases with diabetes, implicating systemic glucose metabolism in joint health. However, a definitive link between cellular metabolism in articular cartilage and OA pathogenesis is not yet established. Here, we report that in mice surgically induced to develop knee OA through destabilization of medial meniscus (DMM), expression of the main glucose transporter Glut1 is notably reduced in joint cartilage. Inducible deletion of Glut1 specifically in the Prg4-expressing articular cartilage accelerates cartilage loss in DMM-induced OA. Conversely, forced expression of Glut1 protects against cartilage destruction following DMM. Moreover, in mice with type I diabetes, both Glut1 expression and the rate of glycolysis are diminished in the articular cartilage, and the diabetic mice exhibit more severe cartilage destruction than their nondiabetic counterparts following DMM. The results provide proof of concept that boosting glucose metabolism in articular chondrocytes may ameliorate cartilage degeneration in OA.

Estradiol Inhibits ER Stress-Induced Apoptosis in Chondrocytes and Contributes to a Reduced Osteoarthritic Cartilage Degeneration in Female Mice

Gender differences are a common finding in osteoarthritis (OA). This may result from a differential response of males and females to endoplasmic reticulum (ER) stress in articular chondrocytes. We have previously described that ER stress in cartilage-specific ERp57 KO mice (ERp57 cKO) favors the development of knee OA, since this stress condition cannot be adequately compensated in articular chondrocytes with increasing age leading to the induction of apoptotic cell death and subsequent cartilage degeneration. The aim of this study was to enlighten gender-specific differences in ER stress, apoptosis, and OA development in ERp57 cKO mice. The analyses were extended by in vitro studies on the influence of estradiol in CRISPR/Cas9-generated C28/I2 ERp57 knock out (KO) and WT cells. ER stress was evaluated by immunofluorescence analysis of the ER stress markers calnexin (Cnx) and binding-immunoglobulin protein (BiP), also referred to as glucose-regulating protein 78 (GRP78) in vivo and in vitro. Apoptotic cell death was investigated by a commercially available cell death detection ELISA and TUNEL assay. OA development in mice was analyzed by toluidine blue staining of paraffin-embedded knee cartilage sections and quantified by OARSI-Scoring. Cell culture studies exhibited a reduction of ER stress and ER stress-induced apoptosis in C28/I2 cells in presence of physiological estradiol concentrations. This is consistent with a slower increase in age-related ER stress and a reduced number of apoptotic chondrocytes in female mice compared to male littermates contributing to a reduced osteoarthritic cartilage degeneration in female mice. Taken together, this study demonstrates that the female sex hormone estradiol can reduce ER stress and ER stress-induced apoptosis in articular chondrocytes, thus minimizing critical events favoring osteoarthritic cartilage degeneration. Therefore, the inhibition of ER stress through a modulation of effects induced by female sex hormones appears to be attractive for OA therapy.

CONSTRUCTION AND ANALYSIS OF MIRNA - MRNA REGULATORY NETWORK IN OSTEOARTHRITIS BASED ON RNA - SEQUENCE DATA

Purpose: Osteoarthritis (OA), as an age-related and disabling joint disease characterized by progressive heterogeneous changes in articular cartilage, subchondral bone, osteophyte formation, has apparently affected 9.6% of males and 18% of females over 60 years old from symptomatic OA, approximately 237 million patients globally. The abnormal expression of mRNA drives an imbalance between catabolic and anabolic factors into osteoarthritic cartilage degeneration. MicroRNAs (miRNAs) are noncoding RNAs of 21-24 nucleotides in length that are widely expressed in eukaryotes and involved in OA progression by regulating the expression of specific targeted genes.

RELATIONSHIP BETWEEN THINNING OF ARTICULAR CARTILAGE DUE TO ENDOCHONDRAL OSSIFICATION AND OSTEOARTHRITIS

Purpose: Our purpose is to evaluate the detailed mechanism of articular cartilage degeneration and thinning in osteoarthritis (OA) according to our hypotheses. In non-decalcified specimens, we detected the subchondral bone plate (Subcho.BP) divided into two layers of non-osteocyte and osteocyte region. In addition, several columnar alignments of chondrocytes were present in the non-osteocyte layer. From these new findings, we hypothesized that articular cartilage thinning is due to endochondral ossification and to the resulting thickening of the non-osteocyte region of the Subcho.BP, which are associated with the onset and progression of OA.

Inhibition of Semaphorin 4D/Plexin-B1 signaling inhibits the subchondral bone loss in early-stage osteoarthritis of the temporomandibular joint

ObjectiveThe aim of this study was to demonstrate the biological function of Semaphorin 4D (Sema4D)/Plexin-B1 in the bone formation features of osteoblasts in early-stage temporomandibular joint (TMJ) osteoarthritis. DesignSema4D/Plexin-B1, expressed by osteoclasts/osteoblasts, plays a balancing role in bone formation and resorption. However, previous studies have mainly focused on bone resorption by osteoclasts in early-stage osteoarthritis. This study used our reported experimental unilateral anterior crossbite (UAC) mouse model to explore subchondral bone changes, which were assessed by micro-CT analysis. The changes in osteoblasts were investigated after the inhibition of Sema4D by BMA-12 injection with the detection of bone formation-related markers. A Transwell migration assay was performed to reveal the specific impact of Sema4D on osteoblasts in vitro. ResultsThe data demonstrated that subchondral bone loss in early-stage TMJ osteoarthritis was accompanied by the upregulated expression of Sema4D in cartilage and subchondral bone and Plexin-B1 in subchondral bone. Reducing Sema4D levels could inhibit subchondral bone loss and cartilage degeneration in early-stage TMJ osteoarthritis. In vitro, the results revealed that Sema4D could reduce the expression of osteocalcin and alkaline phosphatase and increase the migrating capability of Plexin-B1-positive osteoblasts. ConclusionsOur results revealed that elevated Sema4D expression in early-stage TMJ osteoarthritis might decrease the bone formation activity of osteoblasts in the subchondral bone by binding to Plexin-B1 expressed by osteoblasts. Inhibiting Sema4D/Plexin-B1 signaling in early-stage osteoarthritis represents a promising strategy for new therapeutic approaches to osteoarthritis.

G Protein-Coupled Receptors in Osteoarthritis.

Osteoarthritis (OA) is the most common chronic joint disease characterized, for which there are no available therapies being able to modify the progression of OA and prevent long-term disability. Critical roles of G-protein coupled receptors (GPCRs) have been established in OA cartilage degeneration, subchondral bone sclerosis and chronic pain. In this review, we describe the pathophysiological processes targeted by GPCRs in OA, along with related preclinical model and/or clinical trial data. We review examples of GPCRs which may offer attractive therapeutic strategies for OA, including receptors for cannabinoids, hormones, prostaglandins, fatty acids, adenosines, chemokines, and discuss the main challenges for developing these therapies.

Mitochondrial Genome Editing to Treat Human Osteoarthritis-A Narrative Review.

Osteoarthritis (OA) is a severe, common chronic orthopaedic disorder characterised by a degradation of the articular cartilage with an incidence that increases over years. Despite the availability of various clinical options, none can stop the irreversible progression of the disease to definitely cure OA. Various mutations have been evidenced in the mitochondrial DNA (mtDNA) of cartilage cells (chondrocytes) in OA, leading to a dysfunction of the mitochondrial oxidative phosphorylation processes that significantly contributes to OA cartilage degeneration. The mitochondrial genome, therefore, represents a central, attractive target for therapy in OA, especially using genome editing procedures. In this narrative review article, we present and discuss the current advances and breakthroughs in mitochondrial genome editing as a potential, novel treatment to overcome mtDNA-related disorders such as OA. While still in its infancy and despite a number of challenges that need to be addressed (barriers to effective and site-specific mtDNA editing and repair), such a strategy has strong value to treat human OA in the future, especially using the groundbreaking clustered regularly interspaced short palindromic repeats (CRIPSR)/CRISPR-associated 9 (CRISPR/Cas9) technology and mitochondrial transplantation approaches.

Axial alignment is a critical regulator of knee osteoarthritis.

Although osteoarthritis (OA), a leading cause of disability, has been associated with joint malalignment, scientific translational evidence for this link is lacking. In a clinical case study, we provide evidence of osteochondral recovery upon unloading symptomatic isolated medial tibiofemoral knee OA associated with varus malalignment. By mapping response correlations at high resolution, we identify spatially complex degenerative changes in cartilage after overloading in a clinically relevant ovine model. We further report that unloading diminishes OA cartilage degeneration and alterations of critical parameters of the subchondral bone plate in a similar topographic fashion. Last, therapeutic unloading shifted the articular cartilage and subchondral bone phenotype to normal and restored several physiological correlations disturbed in neutral and varus OA, suggesting a protective effect on the integrity of the entire osteochondral unit. Collectively, these findings identify modifiable trajectories with considerable translational potential to reduce the burden of human OA.

Cartilage-Specific Deficiency of Clock Gene Bmal1 Accelerated Articular Cartilage Degeneration in Osteoarthritis by Up-Regulation of mTORC1 Signaling

Cartilage-Specific Deficiency of Clock Gene Bmal1 Accelerated Articular Cartilage Degeneration in Osteoarthritis by Up-Regulation of mTORC1 Signaling

P16INK4a-siRNA nanoparticles attenuate cartilage degeneration in osteoarthritis by inhibiting inflammation in fibroblast-like synoviocytes.

In osteoarthritis (OA), chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favoring disease progression. Although senescence biomarker p16INK4a expression is known to induce aging by halting the cell cycle, therapeutic applications for p16INK4a targeting are limited. Here, we aimed to reduce cartilage damage and alleviate pain using p16INK4a nanoparticles in OA. The p16INK4a expression of human OA chondrocytes and synoviocytes from patients with knee OA was measured and the levels of p16INK4a, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP) 13 were examined. p16INK4a siRNA was encapsulated into poly (lactic-co-glycolic acid) (PLGA) nanoparticles and characterized. The partial medial meniscectomy (pMMx) model was performed for the OA model which was investigated by molecular analysis and behavioral tests. The expression of p16INK4a was increased in the synovium and articular cartilage from OA patients. p16INK4a siRNA-loaded PLGA nanoparticles (p16 si_NP) reduced the levels of TNF-α, IL-1β, and IL-6 especially in fibroblast-like synoviocytes (FLSs), and MMP13 in chondrocytes. Rhodamine-tagged NPs injected into the mouse knee joints were found mainly in the synovium. p16 si_NP injection in the pMMx model alleviated pain-associated behavior, and reduced cartilage damage and p16INK4a in the synovium, and MMP13, collagen X, and NITEGE in cartilage. The preferential reduction of p16INK4a in FLSs by the application of RNAi nanomedicine could contribute to the recovery of osteoarthritic cartilage and relieve pain, suggesting that p16INK4a may be a viable future therapeutic candidate.

Acupuncture Delays Cartilage Degeneration through Upregulating SIRT1 Expression in Rats with Osteoarthritis.

Silent mating type information regulation 2 homolog 1 (SIRT1) has been reported to inhibit osteoarthritic gene expression in chondrocytes. Here, efforts in this study were made to unveil the specific role of SIRT1 in the therapy of acupuncture on cartilage degeneration in osteoarthritis (OA). Specifically, OA was established by the anterior cruciate ligament transection method in the right knee joint of rats, subsequent to which acupuncture was performed on two acupoints. Injection with shSIRT1 sequence–inserted lentiviruses was conducted to investigate the role of SIRT1 in acupuncture-mediated OA. Morphological changes and cell apoptosis in rat OA cartilages were examined by safranin-O staining and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay, respectively. The serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-2 in OA rats were assessed by enzyme-linked immunosorbent assay (ELISA). The expressions of SIRT1, cartilage matrix degradation-related proteins (matrix metalloproteinase (MMP)-9 and ADAMTS5), NF-κB signaling-related markers (p-p65/p65 and p-IκBα/IκBα), and cartilage matrix synthesis-related proteins (collagen II and aggrecan) in the OA cartilage were analyzed by western blot. As a result, acupuncture counteracted OA-associated upregulation of TNF-α, IL-2, cartilage matrix degradation-related proteins, and NF-κB signaling-related markers, morphological damage, apoptosis, SIRT1 downregulation, and loss of cartilage matrix synthesis-related proteins in rat articular cartilages. SIRT1 silencing reversed acupuncture-induced counteractive effects on the aforementioned OA-associated phenomena (except apoptosis, the experiment regarding which under SIRT1 silencing was not performed). Collectively, acupuncture inhibited chondrocyte apoptosis, inflammation, NF-κB signaling activation, and cartilage matrix degradation by upregulating SIRT1 expression to delay OA-associated cartilage degeneration.

ER Stress in ERp57 Knockout Knee Joint Chondrocytes Induces Osteoarthritic Cartilage Degradation and Osteophyte Formation.

Ageing or obesity are risk factors for protein aggregation in the endoplasmic reticulum (ER) of chondrocytes. This condition is called ER stress and leads to induction of the unfolded protein response (UPR), which, depending on the stress level, restores normal cell function or initiates apoptotic cell death. Here the role of ER stress in knee osteoarthritis (OA) was evaluated. It was first tested in vitro and in vivo whether a knockout (KO) of the protein disulfide isomerase ERp57 in chondrocytes induces sufficient ER stress for such analyses. ER stress in ERp57 KO chondrocytes was confirmed by immunofluorescence, immunohistochemistry, and transmission electron microscopy. Knee joints of wildtype (WT) and cartilage-specific ERp57 KO mice (ERp57 cKO) were analyzed by indentation-type atomic force microscopy (IT-AFM), toluidine blue, and immunofluorescence/-histochemical staining. Apoptotic cell death was investigated by a TUNEL assay. Additionally, OA was induced via forced exercise on a treadmill. ER stress in chondrocytes resulted in a reduced compressive stiffness of knee cartilage. With ER stress, 18-month-old mice developed osteoarthritic cartilage degeneration with osteophyte formation in knee joints. These degenerative changes were preceded by apoptotic death in articular chondrocytes. Young mice were not susceptible to OA, even when subjected to forced exercise. This study demonstrates that ER stress induces the development of age-related knee osteoarthritis owing to a decreased protective function of the UPR in chondrocytes with increasing age, while apoptosis increases. Therefore, inhibition of ER stress appears to be an attractive therapeutic target for OA.

The Relationship Between Discoid Meniscus and Articular Cartilage Thickness: A Quantitative Observational Study With MRI.

Background:Several cadaveric imaging studies have demonstrated that the articular cartilage thickness on the tibial plateau varies depending on coverage by native meniscal tissue. These differences are thought to partially contribute to the rates of cartilage degeneration and development of osteoarthritis after meniscectomy. Because there is greater tibial plateau coverage with meniscal tissue in the setting of a discoid meniscus, these findings may also have implications for the long-term health of the knee after saucerization of a torn discoid meniscus.Purpose:To evaluate the relationship between lateral compartment articular cartilage thickness and the presence or absence of a discoid meniscus.Study Design:Cross-sectional study; Level of evidence, 3.Methods:Included in the study were 25 patients younger than 40 years of age who had undergone a 1.5-T or 3-T knee magnetic resonance imaging (MRI) between 2010 and 2016 at a single institution and had an intact, lateral discoid meniscus. Only patients with an otherwise asymptomatic lateral compartment were included. The authors then identified 35 age-matched controls with a nondiscoid, intact lateral meniscus who underwent knee MRI at the same institution and during the same period. The articular cartilage thicknesses in 6 zones of the lateral femoral condyle (LFC) and lateral tibial plateau (LTP) were measured for each patient by 2 musculoskeletal radiologists, and the mean thicknesses were compared between the study and control groups.Results:The average age at MRI was 22.63 years (range, 8.30-35.90 years) for the discoid group and 20.93 years (range, 8.43-34.99 years) for the nondiscoid group. The nondiscoid group had significantly greater mean articular cartilage thickness in all 6 zones of the LTP (P < .05 for all). When comparing the zones of the LFC, there was no significant difference in the mean thickness in any zone between the 2 groups.Conclusion:Patients with discoid menisci had thinner baseline articular cartilage thickness in the LTP compared with those patients without discoid menisci.

Jintiange Capsules Ameliorate Osteoarthritis by Modulating Subchondral Bone Remodeling and Protecting Cartilage Against Degradation.

Osteoarthritis (OA) is the most prevalent joint disease worldwide, making it a major cause of pain and disability. Identified as a chronic and progressive disease, effective treatment at the early stages of OA has become critical to its management. Jintiange (Jtg) capsules are a traditional Chinese medicine produced from multiple organic components of various animal bones and routinely used to treat osteoporosis in China. However, the effect of Jtg on subchondral bone and cartilage degeneration in OA remains unknown. The purpose of the present study was to investigate the biomolecular role and underlying mechanisms of Jtg in OA progression. Herein, we found that Jtg inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation and it functions through the NF-κB signaling pathway. Jtg also inhibited chondrocyte apoptosis via reducing the reactive oxygen species concentration in these cells. Moreover, in vivo evaluation revealed that Jtg significantly attenuates subchondral bone remodeling and cartilage destruction in anterior cruciate ligament transection (ACLT) mouse models. Taken together, our data demonstrate that Jtg inhibits osteoclast differentiation in subchondral bone and chondrocyte apoptosis in cartilage, supporting its potential therapeutic value for treating OA.

IL-33, IL-37, and Vitamin D Interaction Mediate Immunomodulation of Inflammation in Degenerating Cartilage.

Chronic joint inflammation due to increased secretion of pro-inflammatory cytokines, the accumulation of inflammatory immune cells (mainly macrophages), and vitamin D deficiency leads to cartilage degeneration and the development of osteoarthritis (OA). This study investigated the effect of vitamin D status on the expression of mediators of inflammation including interleukin (IL)-33, IL-37, IL-6, tumor necrosis factor (TNF)-α, toll-like receptors (TLRs), damage-associated molecular patterns (DAMPs), and matrix metalloproteinases (MMPs) in degenerating the cartilage of hyperlipidemic microswine. Additionally, in vitro studies with normal human chondrocytes were conducted to investigate the effect of calcitriol on the expression of IL-33, IL-37, IL-6, TNF-α, TLRs, DAMPs, and MMPs. We also studied the effects of calcitriol on macrophage polarization using THP-1 cells. The results of this study revealed that vitamin D deficiency is associated with an increased expression of IL-33, IL-37, IL-6, TNF-α, TLRs, DAMPs, and MMPs, while vitamin D supplementation is associated with a decreased expression of the former. Additionally, vitamin D deficiency is associated with increased M1, while vitamin D-supplemented microswine cartilage showed increased M2 macrophages. It was also revealed that calcitriol favors M2 macrophage polarization. Taken together, the results of this study suggest that modulating expression of IL-33, IL-6, TNF-α, TLRs, DAMPs, and MMPs with vitamin D supplementation may serve as a novel therapeutic to attenuate inflammation and cartilage degeneration in osteoarthritis.

Kartogenin Promotes the BMSCs Chondrogenic Differentiation in Osteoarthritis by Down-Regulation of miR-145-5p Targeting Smad4 Pathway.

Transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for cartilage degeneration of osteoarthritis (OA). But controlling chondrogenic differentiation of the implanted MSCs in the joints remains a challenge. The role of kartogenin (KGN) for chondrogenesis of MSCs has been widely reported, however, the mechanism of chondrogenesis has not been elucidated in OA. In this study, we investigated the miR-145-5p, TGF-β, Samd4, and p-stat3/stat3 expression in cartilage of OA patients and bone marrow mesenchymal stem cells (BMSCs) treated with KGN or miR-145-5p inhibitor. In addition, the cell proliferation and chondrogenic differentiation in vitro and in vivo of BMSCs treated with KGN was also detected. In OA patients, the expression of miR-145-5p was up-regulated, and the expression of TGF-β, Samd4, and p-stat3/stat3 was inhibited. When the BMSCs treated with miR-145-5p inhibitor, the expression of TGF-β, Samd4, and p-stat3/stat3 was also significantly up-regulated. KGN-treated BMSCs had better proliferation and chondrogenic differentiation by up-regulating the expression of Sox 9, Col-2a1, aggrecan in vitro and in OA by down-regulation of miR-145-5p targeting Smad4 pathway. Moreover, intra-articular injection of KGN-treated BMSCs had a better pain relief effect in OA. The double effect on cartilage protection and pain relief indicates a great potential of intra-articular injection of KGN-treated BMSCs for the treatment of OA.

D-mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF-2α-dependent manner.

ObjectivesChondrocyte ferroptosis contributes to osteoarthritis (OA) progression, and D‐mannose shows therapeutic value in many inflammatory conditions. Here, we investigated whether D‐mannose interferes in chondrocyte ferroptotic cell death during osteoarthritic cartilage degeneration.Materials and methodsIn vivo anterior cruciate ligament transection (ACLT)‐induced OA mouse model and an in vitro study of chondrocytes in an OA microenvironment induced by interleukin‐1β (IL‐1β) exposure were employed. Combined with Epas1 gene gain‐ and loss‐of‐function, histology, immunofluorescence, quantitative RT‐PCR, Western blot, cell viability and flow cytometry experiments were performed to evaluate the chondroprotective effects of D‐mannose in OA progression and the role of hypoxia‐inducible factor 2 alpha (HIF‐2 α) in D‐mannose‐induced ferroptosis resistance of chondrocytes.ResultsD‐mannose exerted a chondroprotective effect by attenuating the sensitivity of chondrocytes to ferroptosis and alleviated OA progression. HIF‐2α was identified as a central mediator in D‐mannose‐induced ferroptosis resistance of chondrocytes. Furthermore, overexpression of HIF‐2α in chondrocytes by Ad‐Epas1 intra‐articular injection abolished the chondroprotective effect of D‐mannose during OA progression and eliminated the role of D‐mannose as a ferroptosis suppressor.ConclusionsD‐mannose alleviates osteoarthritis progression by suppressing HIF‐2α‐mediated chondrocyte sensitivity to ferroptosis, indicating D‐mannose to be a potential therapeutic strategy for ferroptosis‐related diseases.

Cutoff points of T1 rho/T2 mapping relaxation times distinguishing early-stage and advanced osteoarthritis.

IntroductionThe histopathology grading system is the gold standard post-operative method to evaluate cartilage degeneration in knee osteoarthritis (OA). Magnetic resonance imaging (MRI) T1 rho/T2 mapping imaging can be used for preoperative detection. An association between histopathology and T1 rho/T2 mapping relaxation times was suggested in previous research. However, the cutoff point was not determined among different histopathology grades. Our study aimed to determine the cutoff point of T1 rho/T2 mapping.Material and methodsT1 rho/T2 mapping images were acquired from 80 samples before total knee replacements. Then the histopathology grading system was applied.ResultsThe mean T1 rho/T2 mapping relaxation times of 80 samples were 39.17 ms and 37.98 ms respectively. Significant differences were found in T1 rho/T2 mapping values between early-stage and advanced OA (p < 0.001). The cutoff point for T1 rho was 33 ms with a sensitivity of 94.12 (95% CI: 80–99.3) and a specificity of 91.30 (95% CI: 79.2–97.6). The cutoff point for T2 mapping was suggested as 35.04 ms with a sensitivity of 88.24 (95% CI: 72.5–96.7) and specificity of 97.83 (95% CI: 88.5–99.9). After bootstrap simulation, the 95% CI of the T1 rho/T2 mapping cutoff point was estimated as 29.36 to 36.32 ms and 34.8 to 35.04 ms respectively. The area under the PR curve of T1 rho/T2 mapping was 0.972 (95% CI: 0.925–0.992) and 0.949 (95% CI: 0.877–0.989) respectively.ConclusionsThe cutoff point of T1 rho relaxation times, which was suggested as 33 ms, could be used to distinguish early-stage and advanced OA.