Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post‐traumatic osteoarthritis

Abstract

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.

Chondroprotective Effects of Combination Therapy of Acupotomy and Human Adipose Mesenchymal Stem Cells in Knee Osteoarthritis Rabbits via the GSK3β-Cyclin D1-CDK4/CDK6 Signaling Pathway

“…It remains to be investigated how combination therapy activates cell cycle regulators. The FAK-PI3K-AKT signaling pathway is a crucial target for the treatment of OA [81]. In previous studies, we demonstrated that acupotomy can promote cartilage anabolism by specially activating the FAK-PI3K-AKT signaling pathway [18].…”

High follicle‐stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF‐κB pathway

“…Allicin alleviates the progression of OA by inactivating the PI3K/AKT/NF-jB pathway [15]. Blocking PI3K/AKT signaling can reduce post-traumatic OA or tumor necrosis factor-a-induced OA [16,17]. Thus, blocking this pathway could be a promising treatment strategy for KOA.…”

PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy‐induced osteoporosis mouse model

“…PI3K/AKT signaling pathway significantly regulates the function of osteoblasts and osteoclasts by influencing the formation, differentiation, proliferation and apoptosis of osteoblasts and osteoclasts (Agas, Sabbieti, Marchetti, Xiao, & Hurley, 2013; Qu et al, 2014). It has been reported that PI3K/AKT signaling pathway maintains the dynamic balance of bone tissue not only under normal conditions, but also under pathological conditions (Lin et al, 2018). Therefore, PI3K/AKT signal pathway was detected by western blot analysis in Kunming mice with osteoporosis and PSMC6 gene knockout mice with osteoporosis caused by ovariectomy, respectively.…”