Hitoshi Suzuki

Oxytocin (OXT) is an endogenous neuropeptide involved in the regulation of nociceptive processing and inflammatory responses. Chronic inflammatory arthritis is characterized by persistent inflammation and pain, and understanding neuroendocrine mechanisms that regulate both processes may provide new insights into the pathophysiology of chronic inflammatory pain. Previous studies have shown that endogenous OXT has both anti-inflammatory and antinociceptive effects, suggesting that activation of the OXT system may influence arthritis by modulating inflammatory and pain-related pathways. However, whether activation of endogenous OXT signaling can modulate the progression of chronic inflammatory arthritis and its associated pain remains incompletely understood. Therefore, this study investigated whether chemogenetic activation of OXT neurons and pharmacological stimulation of OXT receptors modulate disease progression and pain-related outcomes in a rat model of adjuvant arthritis. Adjuvant arthritis was induced in adult male OXT-hM3Dq-mCherry transgenic rats (n = 39) and adult male Wistar rats (n = 10). The transgenic rats were treated with CNO, whereas Wistar rats were treated with LIT-001, with the corresponding vehicle-treated groups serving as controls. Arthritis severity, ankle swelling, mechanical hypersensitivity, joint histopathology, and neuronal activity markers were evaluated. Chemogenetic activation of OXT neurons attenuated arthritis progression during both the onset phase (Days 10-12) and established phase (Days 15-17). During the onset phase, it also reduced ankle swelling and prevented the decline in mechanical nociceptive thresholds. Descriptive histological evaluation showed less pronounced inflammatory cell infiltration, synovial hyperplasia, pannus formation, cartilage destruction, and bone erosion in affected joints. Similarly, repeated administration of the oxytocin receptor agonist LIT-001 ameliorated arthritis severity, joint swelling, and inflammatory pain-related behaviors. Immunohistochemical analyses further revealed increased FosB expression in the paraventricular nucleus and reduced numbers of FosB-immunoreactive and tryptophan hydroxylase (TPH)-immunoreactive cells in the dorsal raphe nucleus following LIT-001 treatment. These findings show that chemogenetic activation of endogenous OXT neurons and administration of the OXT receptor agonist LIT-001 ameliorate arthritis pathology and inflammatory pain-related behaviors in adjuvant arthritis. The OXT system may therefore contribute to the regulation of chronic inflammatory arthritis through coordinated effects on peripheral inflammation and central pain processing.

Background: Transthyretin (TTR) amyloid deposition in the tenosynovium in carpal tunnel syndrome (CTS) is a potential early manifestation of systemic amyloidosis. However, its effects on tenosynovial fibroblasts in CTS remain unclear. We aimed to clarify how wild-type and Val30Met mutant TTR amyloids affect tenosynovial fibroblasts in CTS. Methods: Synovial tissue from 20 patients undergoing carpal tunnel release surgery was evaluated for TTR amyloid. Expression of genes related to fibrosis, inflammation, and oxidative stress was compared between TTR-positive and TTR-negative groups. Fibroblasts isolated from TTR-negative patients were treated in vitro with wild-type or Val30Met mutant recombinant TTR. Analyses included quantitative RT-PCR (reverse transcription-polymerase chain reaction), Picrosirius Red staining, MTT assays evaluating cell proliferation, reactive oxygen species (ROS) activity measurements, and senescence-related gene expression. Results: In TTR-positive tissue, fibrosis-related genes ( COL1A1, COL3A1, TGFB1, and ACTA2 ), the inflammatory mediator NFKB1 , and oxidative-stress-related genes ( KEAP1, NQO1, and SOD1 ) were significantly upregulated, whereas SOD2 was downregulated. With in vitro treatment in the TTR-negative group, both wild-type and Val30Met TTR increased COL3A1, IL6, and CXCL8 expression, whereas Val30Met TTR further enhanced IL1B expression. Picrosirius Red staining confirmed increased collagen deposition. MTT assays revealed increased cell viability, indicating enhanced fibroblast proliferation, in both groups. The senescence-related genes CDKN2D and GADD45A were downregulated, suggesting enhanced proliferative activity. ROS activity did not differ significantly between groups. Conclusions: TTR amyloid was found to promote expression of fibrosis, inflammation, and oxidative-stress-related genes; inhibit senescence pathways; and enhance collagen deposition and fibroblast proliferation in fibroblasts from patients with CTS. Clinical Relevance: CTS with TTR deposition may reflect more than a localized neuropathy, as TTR potentially plays a pathogenic role in CTS development. This finding provides novel insights into the underlying mechanisms of CTS.

Hip fracture is a common injury in older adults; however, the optimal timing of surgical treatment remains undetermined in Japan. Therefore, this retrospective study aimed to ascertain the rate of early surgery among hip fracture patients and investigate its effectiveness, along with “regional clinical pathways” (patient plan of care devised by Japanese clinicians), in reducing the length of hospital stay (LOS) postoperatively. We hypothesized that performing early surgery along with a regional clinical pathway is effective to reduce the postoperative LOS and complications among hip fracture patients. We examined the data of patients diagnosed with femoral neck and peritrochanteric fractures retrieved from the Japanese Diagnosis Procedure Combination database between April 2016 and March 2018. Patients were divided into the early (43,928, 34%; surgery within 2 days of admission) and delayed (84,237, 66%; surgery after 2 days of admission) surgery groups. The difference in postoperative LOS between the two groups was 3 days (early vs. delayed: 29 days vs. 32 days). The early surgery group had more cases of intertrochanteric fractures (57% vs. 43%) and internal fixation (74% vs. 55%) than did the delayed surgery group. In contrast, the delayed surgery group had more cases of femoral neck fractures (43% vs. 57%) and bipolar hip arthroplasty (25% vs. 42%) or total hip arthroplasty (1.2% vs. 3.0%). Moreover, the early surgery group showed a lower incidence of complications, except anemia (12% vs. 8.8%). Logistic regression analysis using the adjusted model revealed that early surgery and implementation of regional clinical pathways reduced LOS by 2.58 and 8.06 days, respectively (p<0.001). Early surgery and implementation of regional clinical pathways for hip fracture patients are effective in reducing postoperative LOS, allowing regional clinical pathways to have a greater impact. These findings will help acute care providers when treating hip fracture patients.

Aims: The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice.Methods: Eight-week-old wild-type (WT) and type 2 diabetic (db/db) mice were divided into four groups without or with metformin treatment (WT met(-/+), Db met(-/+)). Mice received daily intraperitoneal administration of metformin and were killed at 12 and 14 weeks of age. Fibrosis morphology and its related genes and proteins were evaluated. Fibroblasts were extracted from the capsules of 14-week-old mice, and the expression of fibrosis-related genes in response to glucose and metformin was evaluated in vitro.Results: The expression of all fibrosis-related genes was higher in Db met(-) than in WT met(-) and was suppressed by metformin. Increased levels of fibrosis-related genes, posterior capsule thickness, and collagen density were observed in the capsules of db/db mice compared with those in WT mice; these effects were suppressed by metformin. Glucose addition increased fibrosis-related gene expression in both groups of mice in vitro. When glucose was added, metformin inhibited the expression of fibrosis-related genes other than cellular communication network factor 2 (Ccn2) in WT mouse cells.Conclusion: Hyperglycaemia promotes fibrosis in the mouse knee joint capsule, which is inhibited by metformin. These findings can help inform the development of novel strategies for treating knee joint capsule fibrosis.Cite this article: Bone Joint Res 2024;13(7):321–331.

The number of amputated finger replantation has declined in the USA and Germany in recent years; however, there have been no reports on recent trends in Japan. We examined the current practices, attempts, and success factors of digit replantation in Japan. We hypothesized that the rates of digit replantation and success rates were consistently standardized in Japan. The diagnosis procedure combination database was used to analyze 14004 cases from April 2014 to March 2020, excluding multiple-digit amputations, thus focusing on 13484 patients. We evaluated replantation success rates and identified factors influencing replantation decisions using multiple logistic regression analysis. The key findings included a higher frequency of replantation in thumb cases and surgeries during overtime hours, on Sundays, and in educational institutions. Success rates were notably higher for thumb replantations and patients under 20 years of age. Patients over 65 years of age treated with urokinase showed higher failure rates, unrelated to regional or hospital case volumes. The number of amputated digit replantation surgeries in Japan was high during overtime hours, on Sundays, and in educational institutions. Region, hospital type, and hospital case volume were not associated with a low success rate across Japan.

Osteochondritis dissecans (OCD) of the knee is an uncommon injury in young active patients. There is currently a lack of knowledge regarding clinical outcomes and return-to-sport rates after fragment fixation surgery using hydroxy appetite poly-L-lactic acid (HA/PLLA) threaded pins for knee OCD among athletes. Our purpose was to investigate the clinical outcomes and return-to-sport rates following osteochondral fragment fixation using HA/PLLA pins for the treatment of knee OCD lesions among athletes. A total of 45 patients were retrospectively reviewed. In total, 31 patients were excluded, and 14 patients were included. Pre- and postoperative patient-reported outcome scores (PROSs), including the International Knee Documentation Committee (IKDC) score and Knee Injury and Osteoarthritis Outcome Scale (KOOS), were compared. In addition, patients were categorized into four groups according to postoperative sports status: higher, same, lower than preinjury, or unable to return to sports. The mean age was 14.4 years (SD 1.67). All patients were male. All PROSs significantly improved at 6, 12, and 24 months postsurgery compared to presurgery. 50% of the patients returned to sports at the same or higher level after surgery. Fragment fixation using HA/PLLA pins leads to favorable clinical outcome scores and high return-to-sport rates in the treatment of athletes with knee OCD.