INTRODUCTION Osteoarthritis (OA) is a chronic, multicausal, and progressive joint disease that is most common in middleaged and older patients [1-2]. The pathological symptoms of OA involve articular cartilage degeneration and destruction, subchondral bone sclerosis, reactive hyperplasia of the joint edge and subchondral bone, and the formation of osteophytes [3-6]. The pathological changes of OA are mainly characterized by degradation of the cartilage matrix and abnormal anabolism. As the disease progresses, the symptoms of OA are mainly www.aging-us.com
PI3K/AKT signaling is essential in regulating pathophysiology of osteoarthritis (OA). However, its potential modulatory role in early OA progression has not been investigated yet. Here, a mouse destabilization OA model in the tibia was used to investigate roles of PI3K/AKT signaling in the early subchondral bone changes and OA pathological process. We revealed a significant increase in PI3K/AKT signaling activation which was associated with aberrant bone formation in tibial subchondral bone following destabilizing the medial meniscus (DMM), which was effectively prevented by treatment with PI3K/AKT signaling inhibitor LY294002. PI3K/AKT signaling inhibition attenuated articular cartilage degeneration. Serum and bone biochemical analyses revealed increased levels of MMP-13, which was found expressed mainly by osteoblastic cells in subchondral bone. However, this MMP-13 induction was attenuated by LY294002 treatment. Furthermore, PI3K/AKT signaling was found to enhance preosteoblast proliferation, differentiation, and expression of MMP-13 by activating NF-κB pathway. In conclusion, inhibition of PI3K/AKT/NF-κB axis was able to prevent aberrant bone formation and attenuate cartilage degeneration in OA mice.
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