Shiro Imagama’s research while affiliated with Nagoya University and other places

Objectives: This study aims to investigate the association between frailty and oral function in rheumatoid arthritis (RA) patients and to identify practical markers for early frailty detection and potential intervention strategies. Patients and methods: A multi-center observational cohort study (T-FLAG) included a total of 661 RA patients (475 males, 186 females; mean age: 68.5±13.5 years; range, 18 to 100 years) between June 2023 and August 2023. Frailty was assessed using the Kihon Checklist (KCL) (frailty: score ≥8). Oral function scores were based on Question 13 (“difficulty eating hard foods”), Question 14 (“choking”), and Question 15 (“dry mouth”) of the KCL. Receiver operating characteristic (ROC) curves were generated to assess the association between frailty and oral function scores. Multivariate logistic regression was used to analyze factors associated with oral function. Results: Among the 661 participants, 39.5% were frail. Frailty rates tended to increase with increasing oral function scores. The optimal cut-off score for oral function corresponding to frailty was 2 points, with a specificity of 89.2% and a sensitivity of 54.8%. Multivariate analysis identified age and Health Assessment Questionnaire-Disability Index (HAQ-DI) as significant factors associated with oral function decline (i.e., a total score of ≥2 for Questions 13-15 of the KCL). Conclusion: Frailty is strongly associated with oral function decline in RA patients. This finding highlights the importance of monitoring the oral function of RA patients, since it not only reflects physical function, but also serves as a potential marker of frailty. Targeted interventions to improve oral function may play a vital role in reducing frailty risk and enhancing the overall well-being of RA patients.

Objective To compare the effectiveness of methotrexate (MTX) as initial therapy in patients with late-onset and younger-onset rheumatoid arthritis (LORA and YORA). Methods Of 114 patients with YORA and 96 patients with LORA, defined as RA occurring at ≥65 years of age, enrolled in a multicentre RA inception cohort study, 71 and 66 patients who had been followed up to 6 months after starting MTX treatment were included in this study. Results Proportions of patients on MTX treatment at 6 months were 96% and 92% in the YORA and LORA groups, respectively. Despite lower doses of MTX in the LORA group compared with the YORA group, no significant difference was observed in clinical disease activity index scores between the two groups throughout the follow-up period. The proportion of patients in clinical disease activity index remission at 6 months was 35% in both groups. Logistic regression analysis revealed that knee joint involvement and high Health Assessment Questionnaire-Disability Index were significant negative predictors of achieving clinical disease activity index remission at 6 months in the LORA group. Conclusion Observations up to 6 months revealed that the effectiveness of MTX administered based on rheumatologist discretion in patients with LORA is comparable to that in patients with YORA in clinical settings.

The involvement of metabolic reprogramming has been suggested to contribute to the pathophysiology of rheumatoid arthritis (RA). Glycolysis is enhanced in synovial cell metabolism in RA patients. Inhibitors of glycolysis are known to have anti-inflammatory effects. But, changes in the metabolism of normal synovial membranes or synovial cells during the early stages of inflammation remains unknown. Moreover, there are still many aspects of inflammatory signaling pathways altered by glycolysis inhibitors, that remain unclear. In this study we found that, in normal, non-pathological bovine synovial cells, most of ATP synthesis was generated by mitochondrial respiration. However, during the early of stages inflammation, initiated by lipopolysaccharide (LPS) exposure, synovial cells shifted to glycolysis for ATP production. The glycolysis inhibitor 2-deoxyglucose (2DG) reversed LPS induced increases in glycolysis for ATP production and suppressed the expression of inflammatory cytokines and proteolytic enzymes. 2DG suppressed the phosphorylation of the transcription factor cAMP response element binding protein (CREB) enhanced by LPS. Treatment with a CREB inhibitor reversed the expression of LPS-stimulated inflammatory cytokines and proteolytic enzymes. This study showed that changes in metabolism occur during the early stages of inflammation of synovial cells and can be reversed by 2DG and signaling pathways associated with CREB phosphorylation.

Transient receptor potential vanilloid 4 (TRPV4) plays an important role in chondrocytes via Ca ²⁺ signaling. However, its role in the progression of osteoarthritis is unclear. This study aimed to evaluate the effects of TRPV4 activation on articular cartilage and chondrocytes stimulated with interleukin (IL)-1β. Bovine and human articular chondrocytes were stimulated with various agents, including IL-1β, GSK1016790A (GSK101; a TRPV4 agonist), Compound C (an AMP-activated protein kinase (AMPK) inhibitor), and STO-609 (a calmodulin-dependent protein kinase kinase (CaMKK) inhibitor), and were processed for Western blot analysis and real-time PCR. The dimethylmethylene blue (DMMB) assay and Safranin O staining were also performed. GSK101 reversed the IL-1β-induced increase in expression of matrix metalloproteinase (MMP)-13 and decrease in expression of aggrecan. GSK101 also decreased proteoglycan release in the DMMB assay and retained Safranin O staining of articular cartilage tissue. Furthermore, GSK101 increased AMPK phosphorylation and decreased IL-1β-induced nuclear factor kappa B (NF-κB) phosphorylation. Compound C and STO-609 reversed the suppressive effects of GSK101 on NF-κB activation and MMP-13 expression. In conclusion, TRPV4 activation had chondroprotective effects on articular cartilage stimulated with IL-1β by activating CaMKK/AMPK and suppressing the NF-κB pathway. TRPV activators may offer a promising therapeutic option for preventing the progression of osteoarthritis.

Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration for ATP production. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1β-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1β-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.