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Objectives: Ageing and obesity are major risk factors for osteoarthritis (OA), a widespread disease currently lacking efficient treatments. Senescence-accelerated mouse prone 8 (SAMP8) display early onset ageing phenotypes, including OA. This study investigates the impacts of high-fat diet (HFD)-induced obesity on OA development in SAMP8., Methods: SAMP8 at 5 weeks were fed either a normal chow diet or an HFD for 10 weeks to induce obesity. Parameters related to obesity, liver function, and lipid and glucose metabolism were analysed. At 14 weeks of age, knee joint pathology, bone mineral density, and muscle strength were assessed. Immunohistochemistry and TUNEL staining were performed to evaluate markers for cartilage degeneration and chondrocyte apoptosis., Results: At 14 weeks of age, HFD-induced obesity increased liver and adipose tissue inflammation in SAMP8 without further exacerbating diabetes. Histological scoring revealed aggravated cartilage, menisci deterioration, and synovitis, while no further loss of bone mineral density or muscle strength was observed. Increased chondrocyte apoptosis was detected in knee joints following HFD feeding., Conclusions: Ten weeks of HFD feeding promotes spontaneous OA progression in 14-week-old SAMP8, potentially via liver damage that subsequently leads to chondrocyte apoptosis. This ageing-obese mouse model may prove valuable for further exploration of spontaneous OA pathophysiology., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Substance P (SP) modulates NK1 and has various functions such as regulation of pain response, bone metabolism, and angiogenesis, which are recognized as important factors in osteoarthritis (OA). We aimed to evaluate the therapeutic effect of targeting SP on OA progression., Methods: SP expression patterns were analysed histologically in articular cartilage and subchondral bone of human knees from OA patients and autopsy donors as non-OA samples and in mouse articular cartilage. Moreover, to examine the effect of SP on the progression of OA, we administered drugs to mice following the surgical destabilization of the medial meniscus: Phosphate-buffered saline (PBS), septide (NK1 receptor agonist), or aprepitant (NK1 receptor antagonist). Histological analysis and bone morphologic analysis using micro-computed tomography were performed., Results: In human analysis, the expression of SP in mild OA samples was significantly higher than that in severe OA, and that in healthy cartilage was significantly higher than that in OA. In mouse analysis, Osteoarthritis Research Society International scores in the septide group were significantly lower than those in the control group. Computed tomography analysis showed that the subchondral bone's epiphysis in the control group had sclerotic change, not observed in the septide group., Conclusions: The administration of septide ameliorates OA progression through preventing subchondral bone sclerosis., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)