Search

Schematic diagram illustrating the senolytic role of D+Q in lumbar facet joint degeneration [Display omitted] Low back pain (LBP) is a pervasive issue, causing substantial economic burden and physical distress worldwide. Facet joint osteoarthritis (FJ OA) is believed to be a significant contributor to this problem. However, the precise role of chondrocyte senescence in FJ OA remains unclear, as does whether the clearance of chondrocyte senescence can alleviate the progression of FJ OA. The goal of this study was to understand the potential of Dasatinib (D) and Quercetin (Q) as a treatment to clear chondrocyte senescence during the progression of FJ OA. We used a preclinical bipedal standing mice model with the administration of Dasatinib (D) (5 mg/kg) and Quercetin (Q) (50 mg/kg) after 10 weeks of bipedal standing. Human degenerative lumbar facet joint (LFJ) samples were obtained to investigate the relationship between chondrocyte cellular senescence and LFJ osteoarthritis (OA). Subsequently, we established an in vitro model of excessive mechanical stress on chondrocytes and an in vivo bipedal standing mice model to induce LFJ OA. IHC (immunohistochemistry) staining in vivo and SA-β-gal staining, qRT-PCR and Western blot analysis were applied to test the senolytic effect of the combination of Dasatinib (D) and Quercetin (Q). IHC staining and X-ray microscope were also performed to examine the contribution of D+Q to the anabolism in cartilage and subchondral bone recoupling. Immunofluorescence and Western blot analysis in vitro and IHC staining in vivo were conducted to assess the impact of D+Q on the regulation of the NF-κB pathway activation during chondrocyte senescence. We observed that facet joint cartilage degeneration is associated with chondrocyte cellular senescence in both human and mouse degenerative samples. Following treatment with D+Q in vitro, cellular senescence was significantly reduced. Upon oral gavage administration of D+Q in the bipedal standing mice model, decreased cellular senescence and reversed chondrocyte anabolism were observed. Furthermore, administration of D+Q maintained subchondral bone remodeling homeostasis and potentially reversed the activation of the NF-κB pathway in chondrocytes of the lumbar facet joint. In summary, our investigation unveiled a significant correlation between chondrocyte senescence and LFJOA. Treatment with the senolytic combination of D+Q in FJ OA yielded a notable reduction in chondrocyte senescence, along with a decrease in the release of SASP factors. Additionally, it facilitated the promotion of cartilage anabolism, maintenance of subchondral bone coupling, and amelioration of NF-κB pathway activation. Our outcomes revealed that D+Q, the renowned combination used for senolytic treatment, alleviate the progression of LFJ OA. The utilization of D+Q as a senolytic demonstrates a novel and promising alternative for LFJ OA treatment. [ABSTRACT FROM AUTHOR]

Background: Lumbar facet joint osteoarthritis (LFJ OA) is a common disease, and there is still a lack of effective disease-modifying therapies. Our aim was to determine the therapeutic effect of hypoxia-treated adipose mesenchymal stem cell (ADSC)-derived exosomes (Hypo-ADSC-Exos) on the protective effect against LFJ OA. Methods: The protective effect of Hypo-ADSC-Exos against LFJ OA was examined in lumbar spinal instability (LSI)-induced LFJ OA models. Spinal pain behavioural assessments and CGRP (Calcitonin Gene-Related Peptide positive) immunofluorescence were evaluated. Cartilage degradation and subchondral bone remodelling were assessed by histological methods, immunohistochemistry, synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR), and 3D X-ray microscope scanning. Results: Hypoxia enhanced the protective effect of ADSC-Exos on LFJ OA. Specifically, tail vein injection of Hypo-ADSC-Exos protected articular cartilage from degradation, as demonstrated by lower FJ OA scores of articular cartilage and less proteoglycan loss in lumbar facet joint (LFJ) cartilage than in the ADSC-Exo group, and these parameters were significantly improved compared to those in the PBS group. In addition, the levels and distribution of collagen and proteoglycan in LFJ cartilage were increased in the Hypo-ADSC-Exo group compared to the ADSC-Exo or PBS group by SR-FTIR. Furthermore, Hypo-ADSC-Exos normalized uncoupled bone remodelling and aberrant H-type vessel formation in subchondral bone and effectively reduced symptomatic spinal pain caused by LFJ OA in mice compared with those in the ADSC-Exo or PBS group. Conclusions: Our results show that hypoxia is an effective method to improve the therapeutic effect of ADSC-Exos on ameliorating spinal pain and LFJ OA progression. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that by injecting uPA into the lumbar facet joints (LFJ) of normal rats, a rat LFJOA animal model can be successfully established. However, there is no evidence that intraarticular injection of uPA can induce or much serious osteoarthritis in bipedal rats, which biomechanics is much more similar to human than normal rats. To investigate whether intraarticular injection of urinary plasminogen activator (uPA) can induce LFJOA and low back pain symptoms in bipedal rats. Methods: An experimental study on the construction of a modified animal model of lumbar facet joints osteoarthritis (LFJOA) which biomechanics is similar to human. Sprague–Dawley rats were treated with intraarticular injection of uPA in the L5–L6 facet joints (uPA group, n = 15) or saline (saline group, n = 15). The forelimbs of both two group rats were amputated. Mechanical and thermal hyperalgesia in the ipsilateral hind paws were evaluated using von Frey hairs and a thermoalgesia instrument, respectively. Toluidine blue staining, hematoxylin–eosin staining, and immunohistochemical examination of the LFJ was performed. Results: The saline group rats have not demonstrated significant osteoarthritis in rats LFJ after surgery. The uPA group has not been induced significantly higher mechanical and thermal hyperalgesia in comparison with the saline group. But intraarticular injection of uPA in biped rats induced significantly stronger articular cartilage damage, synovitis, and proliferation of synovial cells in the LFJ. Inflammatory factors such as iNOS, IL-1β, and TNF-a were more significantly expressed in bipedal rat injected with uPA (p < 0.05). Conclusions: Intraarticular injection of uPA can induce LFJOA in bipedal rats, while upright posture does not induce osteoarthritis in rats LFJ in the short term. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) is a long-lasting and chronic symptom without any exact cause. This study attempts to propose a new staging system based on the original grading system combined with pathological results and clinical symptoms to better clarify the dynamic evolution of LBP related to cartilage degeneration during facet joint osteoarthritis (FJOA). To explore a potential target for diagnosis, treatment, and drug intervention of facet joint osteoarthritis related LBP via protecting chondrocytes. All the facet joints were divided into 4 groups according to our new degenerative staging system based on Weishaupt grade, CT and MRI. Collect the facet joint samples from patients whom suffered lumbar fusion surgery for lumbar disc herniation. Molecular biology experiments were used to explore the effect of Wnt16 on the degeneration of facet joints. Micro-CT examination and pain stimulation test checked the biological function of Wnt16 in rats. Wnt16 was significantly increased and more aggregated in the facet joint chondrocytes in the Phase III and Phase IV, which is consistent with the pathological findings of cartilage degeneration (OARSI). We found that Wnt16 participated in the regulation of FJOA via Wnt/β-catenin pathway in vitro, which was inhibited by specific inhibitor DKK1. The rats, rich expressed Wnt16, showed higher paw withdrawal thresholds and prolonged paw withdrawal latency to FJOA related LBP. Micro-CT examination for the lumbar spine of rats showed Wnt16 protected the chondrocytes from FJOA. This study defined a new staging system for LBP related cartilage degeneration of facet joint based on the original grading system combined with pathological results and clinical symptoms. Wnt16 is expected to be a potential target for treatment of FJOA via protecting chondrocytes. [ABSTRACT FROM AUTHOR]

Facet joint osteoarthritis (FJOA), a condition commonly observed in individuals of middle to old age, has been relatively under-researched compared to other subtypes of osteoarthritis (OA). This study investigated the role of transcription factor FoxO1 in FJOA using a Col2a1-creERT knock-in mouse model. It was found that FoxO1 deletion led to severe osteoarthritic changes, indicating that FoxO1 played a critical role in cartilage homeostasis. Transcriptome sequencing was performed on degenerated cartilage from FoxO1-deleted mice. This process identified differentially expressed genes (DEGs), offering insights into the molecular mechanisms underlying FJOA. Bioinformatics analysis, including Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) and protein-protein interaction (PPI) network analysis, identified Itgb3, Itga1, Itga6, Itga7, Itga8, Itga10, Col1a1, and Il6, as potential key contributors to FJOA after FoxO1 deletion. Importantly, overexpression of Itgb3 and inhibition of Il6 counteracted FoxO1 knockdown-induced impairments in chondrocyte migration and extracellular matrix synthesis, respectively. This study discovered FoxO1 as a key regulator of the pathogenesis of FJOA, helped unravel the complex molecular mechanisms underlying FJOA, and contributed to the development of promising therapeutic avenues toward FJOA. • FoxO1 deletion results in spontaneous cartilage degradation of FJOA. • Specific FoxO1 Knockout in Facet Joint Cartilage and Movement Behavior Analysis in mice. • FoxO1 knockout induces robust genetic changes. • Identification of key genes in FoxO1L/L Col2a1-creERT mice. • Itgb3 overexpression and Il6 inhibition counteract the biological effects of silenced FoxO1. [ABSTRACT FROM AUTHOR]