SM04690 induced chondrogenesis and appeared to inhibit joint destruction in a rat OA model, and is a candidate for a potential disease modifying therapy for OA.
Methods: Elderly healthy female (128 females) were recruited from the local community. The young healthy female (100 females) were recruited from the department of Rehabilitation and Care of Seijoh University. For each participant, we randomly chose the right or left patella, and assessed their inferior patellar mobility and knee flexion angle. To assess the level of inferior patellar mobility, we used a PFA equipped with a digital caliper. In all cases, measurements were made three times, with the final analysis performed using the mean of those three. We then correlated these two measures with a Japanese Knee Osteoarthritis Measure (JKOM), Visual Analogue Scale (VAS) and Ely's test of the knee. Results: A significant correlation was found in inferior patellar mobility and knee flexion angle in thirty six elderly healthy female (r ¼ 0.72, p < 0.01). However, other data did not have the correlation. Because, there is not the limit of the knee in young healthy female. The inferior patella mobility showed a low value in elderly healthy female (7.5 ± 2.8 mm) in comparison with the young healthy female (15.4 ± 3.7 mm) (p < 0.01). Conclusions: It was found that a reduced knee flexion angle was associated with inferior patellar mobility in the elderly healthy female. It was suggested that inferior patellar mobility decreased by aging.
BACKGROUND CONTEXT: Abnormal Wnt signaling in intervertebral discs (IVDs) progresses degenerative disc disease (DDD) pathogenesis by impairing nucleus pulposus cell function, decreasing matrix deposition, and accelerating fibrosis. PURPOSE: This study was conducted to evaluate the effects of lorecivivint (LOR; SM04690), a small-molecule Wnt pathway inhibitor, on IVD cells and in an animal model of DDD. STUDY DESIGN: We used in vitro assays and a rat model of DDD to test the effects of LOR on nucleus pulposus cell senescence and viability, annulus fibrosus (AF) cell fibrosis, and cartilage regeneration and protection. METHODS: Wnt pathway gene expression was measured in human NP and AF cell cultures treated with LOR or DMSO (vehicle). Chondrocyte-like differentiation of rat and human NP cells, NP cell senescence and protection, and AF cell fibrosis were assessed using gene expression and immunocytochemistry. Disc and plasma pharmacokinetics were analyzed following intradiscal LOR injection in rats. In vivo effects of LOR and vehicle on AF integrity, AF/NP junction, NP cellularity and matrix, and disc height were compared using histopathology and radiography in a rat coccygeal IVD needle-puncture model of DDD. RESULTS: In NP and AF cell cultures, LOR-inhibited Wnt pathway gene expression compared with vehicle. In NP cells, LOR inhibited senescence, decreased catabolism, and induced differentiation into chondrocyte-like cells; in AF cells, LOR decreased catabolism and inhibited fibrosis. A single intradiscal LOR injection in rats resulted in therapeutic disc concentrations (~30 nM) for >180 days and minimal systemic exposure. DDD-model rats receiving LOR qualitatively demonstrated increased cartilage matrix and reduced AF lamellar disorganization and fragmentation with significantly (p<.05) improved histology scores and increased disc height compared with vehicle. CONCLUSIONS: LOR showed beneficial effects on IVD cells in vitro and reduced disease progression in a rat model of DDD compared with vehicle, suggesting that LOR may have diseasemodifying therapeutic potential. CLINICAL SIGNIFICANCE: The current therapeutic options for DDD are pain management and surgical intervention; there are no approved therapies that alter the progression of DDD. Our data support advancing LOR into clinical development as an injectable, small-molecule, potential FDA device/drug status: Not applicable.
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