Session Type: Abstract Submissions (ACR)
Background/Purpose Human knee OA articular cartilage chondrocytes and aged mouse knee cartilage chondrocytes demonstrate decreased activation of master cellular energy bio-sensor AMPK. Moreover, inflammatory stimuli and biomechanical injury induce decreased chondrocyte AMPK activity, which transduces chondrocyte matrix pro-catabolic responses prevented by AMPK pharmacological activators in vitro. Therefore, we tested the hypothesis that activation of AMPK by berberine, an indirect AMPK activator that is employed in traditional medicine and as a dietary supplement, has chondroprotective effect in mice in vivo.
Methods Two groups of male C57BL/6 mice (n=10 for each group), at age 3 months, were subjected to right knee destabilization of media meniscus (DMM) surgery, and left knee sham procedure. After surgery, 1 group was given berberine chloride (10 mg/kg body weight/day) via drinking water, with a no berberine treatment group serving as the control. Mice were sacrificed at 12 weeks after surgery. To study aging-related OA, 2 groups of five 6 month-old male mice were given berberine chloride as above, and 5 age-matched male mice for each group without berberine treatment were used as controls. Mice were sacrificed at age of 18 and 24 months. All mouse joints were fixed, decalcified, embedded in paraffin, and coronally sectioned (5 micron). We harvested 10–12 slides at ~75 micron intervals, and stained with safranin-O and fast green for histologic scoring of the entire articular surface, using the OARSI grading system. Some knee sections also were analyzed by immunohistochemistry (IHC) for expression and -phosphorylation of AMPKα and appearance of NITEGE neoeitope of aggrecanase activity.
Results After DMM surgery, non-treated mice developed OA in the knee medial compartment, with a mean score of 3.72, indicated by loss of safranin-O staining, fibrillation, and partial clefts/erosion down to the calcified cartilage of the articular surface. In comparison, mice receiving berberine treatment after surgery had a marked decrease in OA phenotype in the medial compartment with a mean score of 1.03 (p<0.0001, 95% CI of difference: 1.79 to 3.59). Our aging studies showed aging-related spontaneous OA development in non-treated mice, with mean total joint scores 1.5 and 6.6 (p=0.002, 95% CI of difference: -8.65 to -1.51) for 18 and 24 months-old mice, respectively. In contrast, berberine significantly reduced spontaneous OA development, and particularly so in 24 months-old mice. The mean total joint scores for the berberine treated mice were 0.38 and 2.2 (p=0.008, compared to non-treated mice at 24 months, 95% CI of difference: 0.84 to 7.97) at 18 and 24 months, respectively. Moreover, IHC analysis demonstrated that berberine inhibited both loss of phosphorylation of AMPKa and the appearance of NITEGE neoeitope in articular cartilage.
Conclusion Maintenance of articular chondrocyte AMPK activity by berberine is therapeutically chondroprotective in vivo in mouse knee biomechanical injury and aging models. Targeted activation of AMPK by pharmacologic means, studied here using berberine, provides a novel approach to limiting OA development and progression in mice in vivo, and merits investigation in human OA.
H. S. Lee,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activation-of-amp-activated-protein-kinase-ampk-by-berberine-limits-both-surgical-knee-instability-induced-and-aging-related-osteoarthritis-in-mice/