Differential Production of Proteolytic Enzymes by Normal (KMS-6), Immortally Transformed (KMST-6), and Tumorigenetically Transformed (Ha-KMST-6) Human Fibroblasts

Production of proteolytic enzymes by human fibroblasts in the process of transformation was investigated in order to learn which step, the immortalizing or tumorigenic step, is more important for malignant transformation of human cells. The cells used were normal human fibroblasts (KMS-6), fibroblasts immortally transformed by treatment with Co-60 gamma rays (KMST-6), and KMST-6 cells further tumorigenetically transformed KMST-6 cells by infection with Harvey murine sarcoma viruses (Ha-KMST-6). Proteolytic enzymes in culture medium or cells were assayed using synthetic substrates, N-a-(p-tosyl)-L-arginine [3H]methyl ester hydrochloride and H-D-val-leu-lys-p-nitroaniline. Our results showed that the immortally transformed KMST-6 cells produced a larger amount of the enzymes than the normal and the tumorigenetically transformed cells. Since elevated production of proteolytic enzymes has been reported to correlate well with malignant transformation of cultured rodent or avian cells by many other investigators, our present results indicate that our immortalized human fibroblasts have already acquired properties characteristic to cancer cells

Bisphosphonate use is associated with a decreased joint narrowing rate in the non-arthritic hip

AIMS: The preventive effects of bisphosphonates on articular cartilage in non-arthritic joints are unclear. This study aimed to investigate the effects of oral bisphosphonates on the rate of joint space narrowing in the non-arthritic hip. METHODS: We retrospectively reviewed standing whole-leg radiographs from patients who underwent knee arthroplasties from 2012 to 2020 at our institute. Patients with previous hip surgery, Kellgren-Lawrence grade ≥ II hip osteoarthritis, hip dysplasia, or rheumatoid arthritis were excluded. The rate of hip joint space narrowing was measured in 398 patients (796 hips), and the effects of the use of bisphosphonates were examined using the multivariate regression model and the propensity score matching (1:2) model. RESULTS: A total of 45 of 398 (11.3%) eligible patients were taking an oral bisphosphonate at the time of knee surgery, with a mean age of 75.8 years (SD 6.2) in bisphosphonate users and 75.7 years (SD 6.8) in non-users. The mean joint space narrowing rate was 0.04 mm/year (SD 0.11) in bisphosphonate users and 0.12 mm/year (SD 0.25) in non-users (p < 0.001). In the multivariate model, age (standardized coefficient = 0.0867, p = 0.016) and the use of a bisphosphonate (standardized coefficient = -0.182, p < 0.001) were associated with the joint space narrowing rate. After successfully matching 43 bisphosphonate users and 86 non-users, the joint narrowing rate was smaller in bisphosphonate users (p < 0.001). CONCLUSION: The use of bisphosphonates is associated with decreased joint degeneration in non-arthritic hips after knee arthroplasty. Bisphosphonates slow joint degeneration, thus maintaining the thickness of joint cartilage in the normal joint or during the early phase of osteoarthritis.Cite this article: Bone Joint Res 2022;11(11):826-834

Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

不快感を誘発するセロトニン神経を発見 --セロトニン神経の多様性が明らかに--. 京都大学プレスリリース. 2022-12-23.Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli