Progression Of Osteoarthritis Research Articles

Matrix stiffness in osteoarthritis: from mechanism introduction to biomaterial-based therapies

Osteoarthritis (OA), the most prevalent joint disorder associated with aging, is characterized by impaired extracellular matrix (ECM) synthesis and the degradation of articular cartilage. It is influenced by various factors, including aging and mechanical stress (such as traumatic injury). Increasing evidence suggests that alterations in cartilage stiffness occur during OA progression, particularly at its onset. This review comprehensively examines how aging and mechanical stress contribute to ECM stiffening, a precursor to irreversible cartilage degradation. We also discuss how increased matrix stiffness disrupts the homeostatic balance between chondrocyte catabolism and anabolism and the mechanotransduction pathways involved in cartilage stiffening. Furthermore, the potential of cartilage engineering to target the stiffness of synthetic materials is explored as a promising approach to advancing cartilage repair and regeneration in OA. A deeper understanding of this research area may not only lead to more innovative strategies for early OA detection and diagnosis but also offer novel insights into OA treatment and prognosis.

Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression

BackgroundRecent studies have suggested that targeting senescent cells in joint tissues may alleviate osteoarthritis (OA) progression. However, this strategy encounters significant challenges, partially due to the high degree of cellular heterogeneity in osteoarthritic tissues. Moreover, little information is available on the role of skeletal stem cell (SSC) senescence, as compared to differentiated cells, in OA progression.MethodsIn this study, single-cell RNA sequencing (scRNA-seq) on articular cartilages and subchondral bones of the knee joints of mice with post-traumatic osteoarthritis (PTOA) were performed. Further in vivo and in vitro studies were performed to reveal the role and mechanisims of senescent SSCs during the development of OA lesions and progression by microCT, pathological analysis, and functional gain and loss experiments. The one-way ANOVA was used in multiple group data analysis.ResultsscRNA-seq and pathological data demonstrated that the leptin receptors (Lepr) positive SSCs underwent cellular senescence during OA progression. In addition, the leptin-Lepr signaling pathway induced signal transducer and activator of transcription 3 (STAT3) expression in SSCs, which consequently augmented the transcription of fibroblast growth factor 7 (FGF7). Further scRNA-seq and in vivo analyses revealed that FGF7 exacerbated abnormal bone remodeling in subchondral bones and OA progression by enhancing bone formation and suppressing bone resorption. In vitro analysis revealed that FGF7 induced the osteogenic differentiation of SSCs but inhibited osteoclastogenesis in a concentration-dependent manner.ConclusionsIn summary, our findings demonstrate that the leptin-Lepr signaling pathway promotes SSC senescence and exacerbates subchondral bone remodeling by activating the STAT3-FGF7 axis during OA progression, which may shed light on novel therapeutic strategies for OA.Graphical abstract

Trigonelline Shields Chondrocytes from Oxidative Damage in Osteoarthritis through Activation of the Keap1/Nrf2/ARE Signaling Pathway.

Oxidative stress-induced chondrocyte damage is a key contributor to the progression of osteoarthritis (OA). While trigonelline (TG) possesses anti-inflammatory and antioxidant activities, its functional role and underlying mechanisms in OA remain unclear. In this study, the human chondrocyte cell line CHON-001 was treated with TG alone or in combination with IL-1β or ML385 for 24h. Chondrocyte injury-related events were assessed using Cell Counting Kit-8 (CCK-8), flow cytometry with Annexin V-FITC/PI kit, Hoechst staining, the probe 2,7-Dichlorofluorescin diacetate (DCFH-DA), SA-β-gal staining, and SOD and MDA assay kits. Our data revealed that TG alleviated IL-1β-induced inflammation, apoptosis, extracellular matrix (ECM) degradation, senescence, and oxidative stress in chondrocytes, accompanied by the downregulation of Keap1 and upregulation of Nrf2, HO-1 and NQO1. ML385 treatment reversed the protective effects of TG against IL-1β-induced injury in chondrocytes. In vivo, the anterior cruciate ligament transection (ACLT) was used to induce a rat OA model, and TG was administered by gavage. OA severity and articular cartilage degradation were evaluated by hematoxylin and eosin (H&E), toluidine blue, Safranin-O staining, and Osteoarthritis Research Society International (OARSI) scoring system. The in vivo data showed that TG attenuated the degeneration and erosion of articular cartilage, suppressed inflammation, and downregulated the levels of Keap1 and iNOS, while upregulating the levels of Nrf2 and Col2a1. In conclusion, our study demonstrated that TG inhibits oxidative stress-induced chondrocyte dysfunction and cartilage degradation by activating the Keap1/Nrf2/ARE signaling pathway.

Advanced Injectable Microgels: Porous, Small‐Sized, and Lubricated Systems for Targeted Synergistic Therapy in Osteoarthritis

AbstractMicrogels have attracted increasing attention as drug carriers for osteoarthritis (OA) treatment due to their injectability and modifiability. However, effectively designing high‐efficiency drug‐loading and multifunctional microgel carriers to achieve synergistic therapy of OA remains a challenge. Here, monodisperse, small‐sized, porous, lubricated microgels composed of hyaluronic acid and polysulfomethylacrylate are developed using a multiple Pickering emulsion process. Then, the surface of microgels is modified with the cartilage‐targeting peptide screened through phage display technology to create targeted microgels. The microgels exhibit porosity, small size (≈20 µm) and a swelling ratio of up to 4136.67%, which facilitate efficient loading, targeted delivery, and controlled release of miR‐140, maintaining the metabolic balance of cartilage matrix and inhibiting the development of OA. Additionally, the microgels demonstrate remarkable lubrication performance attributed to the formation of the hydration layer around the hydrophilic groups of the polymers. The in vivo data demonstrate synergistic lubrication and sustained targeted release of miR‐140 by the microgels, resulting in reduced joint wear, decreased osteophyte formation, and effective alleviation of OA progression. This work not only offers a novel method for the preparation of multifunctional microgels, but also lays the foundation for providing new strategies and clinical translation in OA the treatment.

MRI detection of senescent cells in porcine knee joints with a β-galactosidase responsive Gd-chelate

Senescent cells promote osteoarthritis progression through the secretion of inflammatory mediators. Preclinical studies have identified senescence-associated beta-galactosidase (β-gal) as a biomarker of senescence, but in vivo detection remains challenging. Here, we evaluated whether a β-gal responsive gadolinium (Gd) chelate can non-invasively detect β-gal expressing senescent cells with standard clinical magnetic resonance imaging (MRI) technology in vitro, ex vivo, and in vivo in porcine joints. In vitro studies showed that senescent mesenchymal stromal cells (MSCs) exhibited significant MRI signal enhancement upon incubation with the β-gal responsive Gd-chelate compared to viable control cells. In vivo, intraarticular injection of the probe into pig knee joints revealed its retention and activation by senescent cells in cartilage defects, evidenced by a significant increase in R1 relaxation rate. MRI-based senescent cell detection holds promise for identifying patients amenable to senolytic therapies, tailoring treatment plans, and monitoring therapy response in real-time.

Obacunone acts as a histone deacetylase 1 inhibitor to limit p38MAPK signaling and alleviate osteoarthritis progression

BackgroundOsteoarthritis (OA) is an age-related progressive degenerative disorder characterized by cartilage extracellular matrix degradation and inflammation. In this study, we explored the function and mechanism of action of obacunone (OB) in inhibiting OA progression.MethodsThe degradation of articular cartilage and its severity were examined using Safranin O-fast green and hematoxylin and eosin (HE) staining. Chondrocyte survival was evaluated using a cell counting kit-8 assay. In addition, qRT-PCR, western blot analysis, immunohistochemical staining, and enzyme-linked immunosorbent assay were performed to evaluate the effects of OB on cartilage injury.ResultsOB mitigated cartilage lesions in rats with anterior cruciate ligament transaction-induced OA. The protein expression of collagen II was increased and the protein expression of ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS-5), matrix metalloproteinase (MMP)-13, and RUNX family transcription factor 2 (RUNX2) was reduced in the articular cartilage of OB-treated rats. Moreover, OB exhibited anti-inflammatory activities by reducing the serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, and IL-18. In IL-1β-stimulated primary chondrocytes, OB dose-dependently elevated the expression of collagen II, and decreased the expression of ADAMTS-5, MMP-13, RUNX2 and inflammatory cytokines. Histone deacetylase 1 (HDAC1) was identified as a predicted OB target. OB inhibited HDAC1 expression to limit the activation of p38MAPK signaling. The transfection of chondrocytes with HDAC1 or p38MAPK overexpression plasmids reversed the chondroprotective effects of OB.ConclusionOB mitigated OA progression by binding to HDAC1 and inhibiting p38MAPK signaling, indicating that OB may be a promising drug for the treatment of OA.

Functionalized Biomimetic Nanoparticles Targeting the IL‐10/IL‐10Rα/Glycolytic Axis in Synovial Macrophages Alleviate Cartilage Degeneration in Osteoarthritis

AbstractOsteoarthritis (OA) is a low‐grade inflammatory disease that is highly associated with severe hyperplasia of the synovial membrane and the degeneration of cartilage. Interleukin‐10 (IL‐10), has been extensively studied, while its receptor, IL‐10Rα, has not been widely mentioned in the context of OA. A significant difference is found in the expression of IL‐10Rα in synovial macrophages from normal and OA patients, along with a marked increase in the glycolytic activity of synovial macrophages. In IL‐10RαLysm OA mice, the specific deficiency of IL‐10Rα exacerbated the progression of OA. Mechanistically, hypoxia‐inducible factor‐1α (HIF‐1α) is identified as a key transcription factor, and its inhibition significantly weakened the glycolytic process. Additionally, differences in ferroptosis of chondrocytes are observed. After co‐culturing the two types of cells in vitro, a significant connection is found between the glycolytic state of synovial macrophages and the ferroptosis of chondrocytes. To achieve targeted therapy, MI@UN, a biomimetic nanoparticle encapsulating NO‐prednisolone in UIO‐66‐NH2, surface‐modified with IL‐10, and coated with macrophage membranes (MM), is developed. It significantly slows osteoarthritis progression in mice. This offers new insights into OA pathogenesis, highlighting IL‐10Rα as a therapeutic target and supporting MI@UN's translational use for OA treatment.

Abnormal chenodexycholic acid metabolism programming promotes cartilage matrix degradation in male adult offspring rats induced by prenatal caffeine exposure.

Epidemiological evidence links osteoarthritis to fetal origins. Our study shows prenatal caffeine exposure (PCE) in rats predisposes adult offspring to osteoarthritis, associated with elevated intrauterine glucocorticoid levels. Previous research indicates that chenodeoxycholic acid (CDCA), a bile acid, can slow osteoarthritis progression when administered intra-articularly. This study explored if disrupted bile acid metabolism in cartilage affects osteoarthritis risk in adult offspring with PCE. Our findings indicate that the expression of MMP3/MMP13 was upregulated, while endogenous CDCA levels were reduced in the cartilage of PCE-exposed offspring. Furthermore, we observed a persistent reduction in H3K27ac levels at the CYP7B1 promoter and its expression in the cartilage of PCE offspring from fetus to adulthood. Moreover, a sub-physiological level of CDCA promoted NF-κB phosphorylation and the expression of MMP3/MMP13 in chondrocytes in vitro. High levels of glucocorticoids reduced H3K27ac levels and CYP7B1 expression in the promoter region of CYP7B1 through the glucocorticoid receptor and histone deacetylase 4, consequently leading to decreased CDCA levels. In summary, our findings suggest that intrauterine low-expression programming of CYP7B1, induced by elevated glucocorticoid levels, reduces local CDCA levels in the cartilage of PCE offspring, ultimately leading to increased matrix degradation and susceptibility to osteoarthritis.

SHP2-mediated ROS activation induces chondrocyte paraptosis in osteoarthritis and is attenuated by low-intensity pulsed ultrasound.

SHP2-mediated ROS activation induces chondrocyte paraptosis in osteoarthritis and is attenuated by low-intensity pulsed ultrasound.

Therapeutic effect of edaravone on osteoarthritis: targeting NRF2 signaling and mitochondrial function.

Therapeutic effect of edaravone on osteoarthritis: targeting NRF2 signaling and mitochondrial function.

Roles of innate immune system and receptor Dectin-1 in synovium and cartilage homeostasis of osteoarthritis.

Roles of innate immune system and receptor Dectin-1 in synovium and cartilage homeostasis of osteoarthritis.

Mechanism of chondrocyte injury induced by Benzophenone-3 through modulation of the IL-6/JAK2/STAT3 pathway.

Mechanism of chondrocyte injury induced by Benzophenone-3 through modulation of the IL-6/JAK2/STAT3 pathway.

Gut and Joint Microbiomes: Implications in Osteoarthritis.

Gut and Joint Microbiomes: Implications in Osteoarthritis.

Adding Teres Major Transfer to Arthroscopic-Assisted Posterior Latissimus Dorsi Transfer Provides Superior Outcomes for Posterosuperior Irreparable Rotator Cuff Tears.

Adding Teres Major Transfer to Arthroscopic-Assisted Posterior Latissimus Dorsi Transfer Provides Superior Outcomes for Posterosuperior Irreparable Rotator Cuff Tears.

The emerging role of endocannabinoid system modulation in human fibroblast-like synoviocytes: Exploring new biomarkers and potential therapeutic targets.

The emerging role of endocannabinoid system modulation in human fibroblast-like synoviocytes: Exploring new biomarkers and potential therapeutic targets.

MAGI1 attenuates osteoarthritis by regulating osteoclast fusion in subchondral bone through the RhoA-ROCK1 signaling pathway.

MAGI1 attenuates osteoarthritis by regulating osteoclast fusion in subchondral bone through the RhoA-ROCK1 signaling pathway.

Nanomedicine constructed with plant-derived aromatic aldehydes treats low back pain by reversing the progression of lumbar facet joint osteoarthritis

Nanomedicine constructed with plant-derived aromatic aldehydes treats low back pain by reversing the progression of lumbar facet joint osteoarthritis

Rapgef3 modulates macrophage reprogramming and exacerbates synovitis and osteoarthritis under excessive mechanical loading.

Rapgef3 modulates macrophage reprogramming and exacerbates synovitis and osteoarthritis under excessive mechanical loading.

Suppression of experimental knee osteoarthritis by combination therapy of cross-linked hyaluronate and corticosteroids via anti-senescent effects.

Suppression of experimental knee osteoarthritis by combination therapy of cross-linked hyaluronate and corticosteroids via anti-senescent effects.

Mesenchymal stem/stromal cell-derived mitochondria: their role in shaping synovial macrophages and restraining osteoarthritis progression

Mesenchymal stem/stromal cell-derived mitochondria: their role in shaping synovial macrophages and restraining osteoarthritis progression