PLCγ1 deficiency in chondrocytes accelerates the age-related changes in articular cartilage and subchondral bone.

Ageing is the most prominent risk for osteoarthritis (OA) development. This study aimed to investigate the role of phosphoinositide-specific phospholipase Cγ (PLCγ) 1, previously linked to OA progression, in regulating age-related changes in articular cartilage and subchondral bone. d-galactose (d-Gal) was employed to treat chondrocytes from rats and mice or injected intraperitoneally into C57BL/6 mice. RTCA, qPCR, Western blot and immunohistochemistry assays were used to evaluate cell proliferation, matrix synthesis, senescence genes and senescence-associated secretory phenotype, along with PLCγ1 expression. Subchondral bone morphology was assessed through micro-CT. In mice with chondrocyte-specific Plcg1 deficiency (Plcg1flox/flox; Col2a1-CreERT), articular cartilage and subchondral bone were examined over different survival periods. Our results showed that d-Gal induced chondrocyte senescence, expedited articular cartilage ageing and caused subchondral bone abnormalities. In d-Gal-induced chondrocytes, diminished PLCγ1 expression was observed, and its further inhibition by U73122 exacerbated chondrocyte senescence. Plcg1flox/flox; Col2a1-CreERT mice exhibited more pronounced age-related changes in articular cartilage and subchondral bone compared to Plcg1flox/flox mice. Therefore, not only does d-Gal induce senescence in chondrocytes and age-related changes in articular cartilage and subchondral bone, as well as diminished PLCγ1 expression, but PLCγ1 deficiency in chondrocytes may also accelerate age-related changes in articular cartilage and subchondral bone. PLCγ1 may be a promising therapeutic target for mitigating age-related changes in joint tissue.

Associations between CCL21 gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis.

Rheumatoid arthritis (RA) is a chronic systemic disorder characterized by the development through angiogenesis, which is dependent on endothelial cell activation, migration and proliferation and CCL21 plays an important role in this pathology. Currently, CCL21 gene polymorphism studies on rheumatoid arthritis are scarce and the results are diverse. This meta-analysis was performed to determine if CCL21 gene polymorphisms correlate with the risk of developing RA. Association reports for the relationship between CCL21 polymorphisms and RA were identified from PubMed, Cochrane Library, Embase, SCIELO, CNKI and Wanfang databases on March 22, 2017. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the relationship strength. Publication bias was conducted with Begg's funnel plot and Egger's regression test to measure the robustness of our findings. Sensitivity and cumulative analyses were used to assess the overall robustness of the study's results. Four relevant case-control cohort studies and three GWAS studies with CCL21rs2812378G>A gene polymorphisms and rheumatoid arthritis involving 9963 RA cases and 7976 controls were identified. Significant associations between the CCL21 rs2812378G>A polymorphism and RA risk were observed in the co-dominant model, dominant model and heterozygous model (A vs G: OR = 1.08, 95% CI = 1.03-1.14, p < 0.01, I 2 = 0.0%; AA + AG vs GG: OR = 1.15, 95% CI = 1.05-1.28, p < 0.01, I 2 = 0.0%; AG vs GG: OR = 1.18, 95% CI = 1.08-1.30, p < 0.01, I 2 = 3.8%) in the total population, as well as in subgroup Caucasian population. The combined analysis revealed a significantly increased risk of rheumatoid arthritis in the co-dominant model, dominant model and heterozygous model in overall population and subgroup Caucasian population.

Impaired autophagy contributes to the aggravated deterioration of osteoarthritis articular cartilage by peroxisome proliferator-activated receptor α deficiency, associated with decreased ERK and Akt activation.

BACKGROUND: Although the chondroprotection of peroxisome proliferator-activated receptor α (PPARα) activation against osteoarthritis (OA) has been revealed, the regulatory mechanism of PPARα deficiency to aggravate osteoarthritic cartilage deterioration remains unclear. Here, we aimed to investigate whether and how autophagy is involved in OA pathological progression. METHODS: Model of experimental OA was established using destabilization of the medial meniscus in PPARα-KO 129S4/SvJae male mice, followed by histopathological detection of articular cartilage and immunohistochemistry detection of extracellular matrix (ECM) or autophagy-related signal molecules. Meanwhile, human OA chondrocytes obtained from total knee replacement surgery patients with OA were cultured with the pretreatment of IL-1ß, followed with the treatment of PPARα agonist WY14643 and the detection of related signal molecules. RESULTS: PPARα deficiency aggravated cartilage damage with decreased LC3B level in combination with an increase in P62 level, accompanied with reduced p-Akt and p-ERK levels in PPARα-KO mouse model of experimental OA. On the contrary, PPARα activation by WY14643 promoted ECM synthesis in IL-1ß-treated human OA chondrocytes, accompanied with increased LC3B-II/I ratio and Beclin 1 level and decreased P62 and Bcl2 levels. Meanwhile, it was observed that activated ERK and Akt by PPARα activation contributed to the enhancement of autophagy and ECM synthesis in human OA chondrocytes. CONCLUSIONS: Impaired autophagy contributed to the aggravated deterioration of osteoarthritis articular cartilage by PPARα deficiency associated with the suppression of ERK and Akt, with an implication that triggering PPARα activation ought to be a potential promising therapeutic target for OA therapy.

Follow-up frequency and clinical outcomes in patients with type 2 diabetes: A prospective analysis based on multicenter real-world data.

BACKGROUND: To determine whether the follow-up frequency for type 2 diabetes mellitus (T2DM) patients in the National Metabolic Management Centers (MMCs) leads to different clinical outcomes. METHODS: A total of 19 908 T2DM patients with at least 6 months of facility-based follow-up were recruited in MMCs between June 2017 and April 2021 and divided into lower-frequency and higher-frequency follow-up (LFF and HFF) groups according to the median follow-up frequency of 2.0 (interquartile range 1.2) times per year. Metabolic parameters at baseline and at the last follow-up visit were analyzed. Multivariable linear regression models were performed to assess the relationship between follow-up frequency and between-group percentage changes, adjusting for the major covariables. Additional stratified analyses were conducted to evaluate the metabolic outcomes in the subgroups. RESULTS: The characteristics of the participants in the LFF and HFF groups were significantly different at baseline. Participants had significant improvements in multiple metabolic parameters after follow-up. Patients with HFF showed significantly greater decrease in percentage changes of fasting blood glucose (-4.95% ± 37.96% vs -2.21% ± 43.08%, P < .0001) and glycosylated hemoglobin (HbA1c) (-12.14% ± 19.78% vs -9.67% ± 20.29%, P < .0001) after adjustments compared to those with LFF. Furthermore, stratification analyses showed that significant between-group percentage changes of HbA1c were observed in those with younger age (<55 years) and higher HbA1c (>9%) at baseline (P for interaction <.001). CONCLUSIONS: HFF is associated with better metabolic outcomes. Participants, especially with younger age or worse HbA1c at baseline in the HFF group achieved better glycemic control than those in the LFF group.