Osteoarthritis and Cartilage最新文献

Objective: Fibroblast growth factor (FGF) signaling plays a significant role in osteoarthritis (OA) pathogenesis, though the OA-related functions of only a few FGFs have been fully elucidated. This study investigates the specific roles of FGF7 in OA development.

Methods: FGF7 expression was analyzed in human (n=6) and mouse (n=10) cartilage. Experimental OA was induced by destabilization of the medial meniscus (DMM). The roles of FGF7 were explored using intra-articular (IA) injection of recombinant FGF7 (rFGF7) and whole-body Fgf7 knockout mice (Fgf7^-/-). Subchondral bone remodeling and growth plate morphology were assessed micro computed tomography (µCT) and histological analysis.

Results: FGF7 was upregulated in OA cartilage. IA injection of rFGF7 led to OA cartilage destruction (OARSI [Osteoarthritis Research Society International] grade; 0.61 [95% CI 0.00-5.33]), while Fgf7^-/- mice showed reduced DMM-induced cartilage erosion (OARSI grade; 1.89 [95% CI 1.08-3.00]) compared to wild-type mice (4.92 [95% CI 3.83-5.33]). These effects were associated with changes in matrix-degrading enzyme expression in chondrocytes. Mice receiving IA injection of rFGF7 (20 μg) exhibited increased subchondral bone thickness (68.01 µm [95% CI 61.55-74.46]) and decreased osteoclastogenesis (tartrate-resistant acid phosphatase positivity; 1.94% [95% CI 1.41-2.47]) compared to controls (38.33 µm [95% CI 33.71-42.96]) and (4.23% [95% CI 3.28-5.19]), respectively. Additionally, rFGF7 treatment caused premature closure of growth plates, whereas Fgf7^-/- mice exhibited significantly increased growth plate thickness.

Conclusions: FGF7 exerts multiple functions in various joint tissues, including promoting cartilage destruction, inducing subchondral bone remodeling (SBP thickening), and triggering premature growth plate closure.

Background: Intervertebral disc degeneration (IVDD) is a natural process that occurs with aging and is the main cause of low back pain. Basic helix-loop-helix ARNT-like 1 (BMAL1) plays key roles in the pathogenesis of many diseases. The present study investigates the role of curculigoside (CUR), which has been reported to be a potential anti-apoptotic compound in other diseases.

Methods: Dysregulated genes were identified by RNA sequencing (RNA-seq). Western blotting (WB), immunohistochemistry, immunofluorescence (IF) staining, and real-time fluorescent quantitative polymerase chain reaction were used to detect BMAL1 expression in 25 human intervertebral disc specimens (male: female =13:12), tissues from BMAL1-knockout mice and from an IVDD mouse model. The regulatory effects of CUR and BMAL1 in nucleus pulposus (NP) cells after Small Interfering RNA (siRNA) transfection were examined by flow cytometry, IF staining and WB. The therapeutic effect of intraperitoneal CUR injection was also evaluated in mice.

Results: BMAL1 expression was negatively correlated with IVDD severity and was significantly lower in degenerative NP cells. After BMAL1 knockdown using siRNA, the apoptosis rate of degenerative NP cells was significantly higher, while transfection with a lentivirus overexpressing BMAL1 exerted the opposite effect. Bioinformatics analysis revealed that BMAL1 is regulated by the JAK-STAT3 pathway, and CUR upregulated BMAL1 expression by inhibiting STAT3 phosphorylation, subsequently alleviating NP cell apoptosis and increasing extracellular matrix (ECM) components., thus alleviating IVDD.

Conclusions: CUR can inhibit apoptosis and improve the ECM by upregulating BMAL1 expression, which is reduced in IVDD. This study provides a therapeutic strategy to alleviate apoptosis associated with inflammation-induced IVDD.

Objective: Compare prevalence and changes in outcomes among established and early-stage knee osteoarthritis (KOA) patients undertaking supervised exercise and education.

Methods: Patients from Good Life with osteoArthritis in Denmark (GLA:D®) were stratified into three groups: established KOA (ACR/EULAR criteria), early-stage KOA (diagnostic-model-outcome ≥70%, Criteria for the Early Diagnosis of knee Osteoarthritis) or potential early-stage KOA (diagnostic-model-outcome 30-69%). Mixed-effects models and the proportion of patients by group achieving minimal clinically important improvements (MCIIs) were used to investigate changes in VAS pain intensity (0-100mm), Knee injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QoL; 0-100), 40 m Walk test and 30 s chair-stand test at 3 and 12 months.

Results: Compared to established KOA (61% of 10,365 patients), early-stage KOA (27%) had similar knee pain at baseline (mean (standard deviation); 51 (22) vs 45 (22)), and improvement in pain (mean (95% CI) -15 (-15 to -14) vs -14 (-15 to -13), ≥MCII: 55% vs 54%) and KOOS QoL (≥MCII: 50% vs 50%) at 12 months, and in walking speed (≥MCII: 56% vs 52%) and chair-stands (≥MCII: 55% vs 52%) at 3 months. Compared to either group, potential early-stage KOA (10%) had lower baseline pain (34 (32.7)) and less improvement in pain (-9.8 (-11.3 to -8.2; ≥MCII: 47%)), but comparable improvements in KOOS QoL (≥MCII: 50%), walking speed (≥MCII: 51%) and chair-stands (≥MCII: 51%).

Conclusion: Patients with early-stage KOA achieved comparable improvements at 3 and 12 months to those with established KOA, supporting supervised exercise and education as a viable management strategy for early-stage KOA.

Objective: Conventional methodologies are ineffective in predicting the rapid progression of knee osteoarthritis (OA). MicroRNAs (miRNAs) show promise as biomarkers for patient stratification. We aimed to develop a miRNA prognosis model for identifying knee OA structural progressors/non-progressors using integrated machine/deep learning tools.

Methods: Baseline serum miRNAs from Osteoarthritis Initiative (OAI) participants were isolated and sequenced. Participants were categorized based on their likelihood of knee structural progression/non-progression using magnetic resonance imaging and X-ray data. For prediction model development, 152 OAI participants (91 progressors, 61 non-progressors) were used. MiRNA features were reduced through VarClusHi clustering. Key miRNAs and OA determinants (age, sex, body mass index, race) were identified using seven machine learning tools. The final prediction model was developed using advanced machine/deep learning techniques. Model performance was assessed with area under the curve (AUC) (95% confidence intervals) and accuracy. Monte Carlo cross-validation ensured robustness. Model validation used 30 OAI baseline plasma samples from an independent set of participants (14 progressors, 16 non-progressors).

Results: Feature clustering selected 107 miRNAs. Elastic Net was chosen for feature selection. An optimized prediction model based on an Artificial Neural Network comprising age and four miRNAs (hsa-miR-556-3p, hsa-miR-3157-5p, hsa-miR-200a-5p, hsa-miR-141-3p) exhibited excellent performance (AUC, 0.94 [0.89, 0.97]; accuracy, 0.84 [0.77, 0.89]). Model validation performance (AUC, 0.81 [0.63, 0.92]; accuracy, 0.83 [0.66, 0.93]) demonstrated the potential for generalization.

Conclusion: This study introduces a novel miRNA prognosis model for knee OA patients at risk of structural progression. It requires five baseline features, demonstrates excellent performance, is validated with an independent set, and holds promise for future personalized therapeutic monitoring.

Objective: We test whether the specialized pro-resolving molecule Maresin 1 (MaR1) attenuates nociceptive behaviors in mice with osteoarthritis-like pain.

Design: Osteoarthritis (OA)-like pain behavior was induced by intra-articular injection of monosodium iodoacetate (MIA) and treated with MaR1 (N=6) or vehicle (N=5) by intraperitoneal injection 8 weeks after injury. Mice without MIA injection were used as control (N=6). Nociceptive behaviors were examined by von Frey and dynamic weight bearing measurements. Calcitonin gene-related peptide (CGRP) expression and activated macrophages in the dorsal root ganglion (DRG) were examined by immunofluorescence staining. The inflammatory profile in circulation was assessed by cytokine array. Calcium imaging was performed to assess the in vitro functional response of DRG neurons from animals with OA-like pain behavior to MaR1 with or without RAR Related Orphan Receptor A (RORA) inverse agonist SR3335.

Results: MaR1 attenuated knee pain behavior in treated mice (N=6) compared to non-treated mice (N=5) as shown by increased paw withdrawal threshold with a mean difference of 112.2% (95% CI [49.79, 174.6], p=0.0784) at 4 h and 150.9% (95% CI [104.2, 197.5], p=0.0001) at 4 days post-MaR1 treatment, and increased weight bearing with a mean difference of 20.08% (95% CI [2.798, 37.37], p=0.0277) at 1 day post-MaR1 treatment. CGRP expression and activated macrophages were decreased in the DRG, and inflammatory cytokine levels in the circulation were attenuated. Calcium imaging showed MaR1 reduced the functional response of DRG neurons through RORA.

Conclusions: Our results show that MaR1 reduces OA-like pain behavior in mice and could be a potential treatment for OA pain.

Objective: To estimate the size of regression to the mean (RTM) for common patient-reported outcomes in trials for knee osteoarthritis (OA).

Design: Longitudinal cohort study; we included participants of the Osteoarthritis Initiative who fulfilled typical inclusion criteria for enrolment in a trial. These included: age 40-79 years, symptomatic knee OA, Kellgren-Lawrence grade 2-3, use of pain medication more than half the days of a month in past 12 months, numerical rating scale pain of 4 to 9. We studied observed changes in WOMAC physical function and KOOS quality of life (QOL).

Results: We identified 547 subjects who fulfilled inclusion criteria on at least one annual follow-up between year 1 and year 8. The mean level of physical function and QOL at each follow-up time point was similar, about 18 and about 51, respectively. However, at the time of theoretical inclusion in a trial, the mean levels in the same subjects were 23 and 43, respectively (both worse scores). The mean improvement in physical function between inclusion and 1 and 2 years later, respectively, was 2.5 (95% confidence interval 1.7 to 3.2) and 3.1 (2.3 to 3.8). The corresponding improvement in QOL was 2.7 (1.7 to 3.7) and 4.2 (3.1 to 5.3).

Conclusion: RTM in trials for knee OA is likely to explain improvement in physical function and QOL, not only in knee pain. RTM often misleads investigators to overinterpret effectiveness as RTM neither represents improvement from the intervention nor placebo effect from the intervention and its context.

Objectives: Previous genetic and animal studies indicated a causal role of thyroid hormones in osteoarthritis (OA), which has not been observed in the general population. We aimed to investigate whether thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were associated with hand, hip, or knee OA.

Methods: Participants from the Rotterdam Study with baseline TSH, FT4, and joint radiographs were included. We used multivariable regression models to investigate the association of thyroid function with the prevalence, severity, incidence, and progression of OA. We conducted stratified analyses by sex, age, body mass index (BMI) and weight-bearing physical activity.

Results: Among 9054 participants included (mean age 65 years, 56.3% women), higher FT4 concentrations were associated with an increased risk of prevalent knee OA (odd ratio [OR] 1.04 per pmol/L, 95% CI 1.01-1.06, corresponding to an OR of 1.62 across the reference range [i.e., 14pmol/L changes] of FT4) and more severe knee OA. There was a positive association between FT4 and overall progression of knee OA (OR 1.03 per pmol/L, 1.00-1.07). No association of TSH with hand, hip, or knee OA was identified. Stratified analysis revealed an association between FT4 and prevalent knee OA among individuals with BMI ≥30 kg/m² (OR 1.05 per pmol/L, 1.01-1.08) and those with high levels of weight-bearing physical activity (OR 1.05 per pmol/L, 1.01-1.10).

Conclusions: Our study indicated that higher FT4 concentrations may increase the risk of knee OA. This association might be greater in individuals with extra joint loading, such as those with obesity.