Osteoarthritis and Cartilage最新文献

Objective: Low back pain (LBP) is one of the most prevalent musculoskeletal disorders and has a significant global impact. Intervertebral disc degeneration (IVDD) is an important cause of LBP. The aim of this study was to test a hypothesis that elucidates the potential role and molecular mechanisms of cytokine receptor-like factor 1 (CRLF1) in IVDD and LBP.

Methods: We identified dysregulated genes in normal and degenerative discs via microarray profiles. We verified the correlation between CRLF1 and the progression of IVDD in animal models and cellular models and further explored the effect of increased CRLF1 on nucleus pulposus cells (NPCs) and its mechanism by RNA-seq. Finally, the ameliorative effect of CRLF1 knockdown on degenerated NPCs was elucidated by in vivo and in vitro experiments.

Results: We verified the close relationship between senescent NPCs and IVDD. We determined that elevated CRLF1 is associated with the progression of NPC senescence and IVDD in animal and cellular models. In addition, fluorescence colocalization and coimmunoprecipitation analysis revealed that CRLF1 forms a heterodimer with cardiac dystrophin-like cytokine 1 (CLCF1), which together activate JAK/STAT3 signaling. This activation enhances the production of senescence-associated secretory phenotype (SASPs) and accelerates NPC senescence. In vitro studies have shown that targeting CRLF1 reduces extracellular matrix (ECM) degradation and alleviates NPC senescence. Correspondingly, in vivo and pain-behavior tests showed that CRLF1 knockdown reduces IVDD and LBP.

Conclusion: The CRLF1/CLCF1 heterodimer is involved in IVDD, and CRLF1 may be an effective therapeutic target for treating IVDD progression and associated LBP.

Objective: To explore the mechanism of action and structural effects of MM-II, a dispersion of "empty" multilamellar large liposomes composed of dimyristoyl phosphatidylcholine (DMPC) and dipalmitoyl phosphatidylcholine (DPPC), which durably reduced pain in a phase 2b study in knee osteoarthritis (OA) patients.

Method: MM-II liposomes were manufactured using a defined ratio of DMPC and DPPC, resulting in a lipid phase transition temperature range overlapping with the temperature of human OA knees. MM-II cartilage coating in the presence and absence of compression load was assessed using labeled MM-II. Lubrication of damaged cartilage by MM-II was tested in cartilage-on-glass friction tests and pin-on-disc wear tests. Knee distribution of intra-articularly injected MM-II was assessed in healthy and OA rabbit knees. Structural effects were assessed using a rat OA model comparing to DPPC liposomes, DMPC liposomes, a mixture of DPPC and DMPC liposomes, and vehicle.

Results: In a pin-on-disc model, MM-II reduced cartilage wear by up to 44% compared to control. MM-II liposomes bound to cartilage discs preferentially under compression load. Coating of cartilage and menisci with MM-II was also observed in both healthy and OA rabbit knees. Cartilage-bound MM-II efficiently lubricated damaged cartilage discs. In a rat OA model, MM-II demonstrated 53% reduction in tibial cartilage degeneration and the least associated mononuclear cell recruitment compared to other groups.

Conclusions: Reduction in cartilage degeneration by MM-II in OA rats is likely mediated through formation of a lubricative layer at the cartilage surface, though additional mechanisms could be mediating pain reduction demonstrated in clinical trials.

Objective: To investigate the interaction among the cells thought to be foundational to inflammation, fibrosis, and angiogenesis in the synovial membrane.

Method: We encapsulated fibroblasts, polarized macrophages, and endothelial cells in a 3D culture system. We used this model to determine the cellular transcriptional profiles, cytokine secretion, and vascular formation associated with different macrophage phenotype conditions.

Results: Neo-angiogenesis reached its maximum level at approximately day 21 in the presence of pro-inflammatory macrophages conditions, but was sustained in the presence of anti-inflammatory macrophages. RNA sequencing revealed an influence of macrophage phenotype on gene expression associated with fibrosis and angiogenesis. Furthermore, by including lipopolysaccharides-coated polyethylene particles (lcPE), an inflammatory stimulus replicating wear debris from joint replacements into our system, insights into the local reaction to byproducts of different biomaterials can be ascertained.

Conclusion: Chronic inflammation and fibrosis of the synovial membrane are often present in osteoarthritis and post-total joint arthroplasty. Our results suggest that the progression of inflammatory synovial diseases is influenced by macrophage phenotypes.

Objective: Abnormal mechanical stress is a key factor in osteoarthritis (OA) pathogenesis. This study aims to investigate the role of the mechanosensitive ion channel Piezo1 in activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and its contribution to cartilage degradation in OA.

Methods: We conducted both in vivo and in vitro experiments. In vitro, chondrocytes were subjected to mechanical stress, and Piezo1 expression, calcium ion (Ca²⁺) influx, and mitochondrial permeability changes were analyzed. In vivo, Piezo1 conditional knockout (Col2a1^CreERT; Piezo1^flox/flox) mice were used to assess the activation of the cGAS-STING pathway and cartilage degradation. Additionally, the effects of STING inhibitors on inflammation and OA progression were evaluated.

Results: Mechanical stress significantly increased Piezo1 expression and Ca²⁺ influx in chondrocytes, leading to mitochondrial Ca²⁺ overload and mitochondrial DNA (mtDNA) release. This triggered activation of the cGAS-STING pathway (9.35[95%Confidence Interval (CI) 1.378 to 18.032], n=3 biologically independent samples), resulting in inflammatory responses (4.185[95%CI 0.411 to 8.168], n=3 biologically independent samples). In Piezo1 knockout mice, cGAS-STING activation (-7.23[95%CI -10.52 to -3.89], n=6) and cartilage degradation (Osteoarthritis Research Society International (OARSI) grade; -3.651[95%CI -5.562 to -1.681] n=6) were reduced. STING inhibitors effectively decreased inflammation (-8.95[95%CI -17.24 to -1.31], n=3 biologically independent samples) and slowed OA progression (OARSI grade; -2.76 [95%CI -4.37 to -1.08], n=6) in both in vivo and in vitro models.

Conclusions: Mechanical stress induces mtDNA release via Piezo1 activation, which triggers the cGAS-STING pathway and exacerbates cartilage degradation. Targeting Piezo1 or the cGAS-STING pathway may offer a promising therapeutic strategy to reduce inflammation and protect cartilage in OA.

Objective: Small studies in athletes showed that primary cam morphology (PCM) gradually develops during skeletal growth. However, the prevalence of PCM in early adolescents is poorly understood. We aimed to estimate the overall and birth-assigned sex-specific prevalence of PCM in early adolescents from the general population.

Design: We cross-sectionally analyzed data from the Generation R cohort, an ongoing population-based prospective cohort study from early fetal life onward from Rotterdam, the Netherlands. High-resolution dual-energy x-ray absorptiometry scans were performed on the right hip of participants around the age of 13 years. The alpha angle (AA) and triangular index ratio (TIR) were automatically measured. We defined PCM by a validated AA threshold ≥ 60° or a TIR threshold ≥ 1.05. The overall and birth-assigned sex-specific prevalence of PCM was reported as a percentage with 95% confidence interval (CI).

Results: The median age of the 4477 early adolescents included in this analysis was 13.5 years (2.5th - 97.5th percentile, 13.2 - 14.6) with 2166 (48.4%) being males. The overall prevalence of PCM (AA ≥ 60° or TIR ≥ 1.05) was 3.5% (95% CI, 2.9-4.0%). Male and female adolescents had a similar prevalence of PCM: 3.9% (95% CI, 3.1-4.7%) vs 3.0% (95% CI, 2.3-3.7%).

Conclusions: The overall prevalence of PCM was 3.5% in early adolescents from the general population in the Netherlands. The prevalence of PCM was similar between male and female early adolescents.

Objective: Senescent nucleus pulposus mesenchymal stem cells (NPMSCs) are key instigators of local chronic inflammation and disruptions in nucleus pulposus tissue repair in intervertebral disc degeneration (IVDD). This study aimed to investigate the interplay between EZH2 and NPMSCs senescence-associated inflammation.

Methods: Nucleus pulposus samples were collected from IVDD patients (n = 15, F/M = 7/8, average age 47.9 (21-72) year-old). Multiplex immunohistochemistry was conducted to detect the expression of EZH2 and the cGAS/STING pathway. Subsequently, NPMSCs were isolated from 7 patients (n = 7, F/M = 4/3, average age 49.4 (36-68) year-old). After treatment with tert-butyl hydroperoxide and lentivirus-overexpression-EZH2 (Lv-OE-EZH2), real time fluorescent quantitative PCR, immunofluorescence, western blot, and ChIP were used to detect the expression of EZH2 and the cGAS/STING pathway. Micro-CT, magnetic resonance imaging, and histological staining were performed to assess the therapeutic effects of Lv-OE-EZH2 and a STING inhibitor on rat IVDD. All experiment designs were independent.

Results: In both human nucleus pulposus tissues and an in vitro cell model, EZH2 expression decreased while the cGAS/STING pathway became activated in senescent NPMSCs. ChIP assays and Lv-OE-EZH2 experiments validated that EZH2 epigenetically inhibited STING expression via H3K27me3, thereby impairing the cGAS/STING pathway and attenuating senescence-associated inflammation. Moreover, overexpression of EZH2 (Pfirrmann grade means difference -1.375, p = 0.0089) and inhibition of STING effectively attenuated rat IVDD.

Conclusion: The decreased expression of EZH2 in senescent NPMSCs promotes senescence-associated inflammation and the progression of IVDD, possibly by relieving the transcriptional inhibition of STING and enabling the activation of the cGAS/STING pathway.