Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 233, Issue 8, Pages 6135-6147Publisher
WILEY
DOI: 10.1002/jcp.26460
Keywords
articular cartilage; osteoarthritis; PI3K; AKT signaling; preosteoblasts; subchondral bone
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Funding
- National Natural Science Foundation of China [81371990, 81601945]
- Science and Technology Planning Project of Guangdong Province [2015ZC0020]
- Australian National Health and Medical Research Council (NHMRC) [1094606]
- NHMRC Senior Research Fellowship [1042105]
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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-B pathway. In conclusion, inhibition of PI3K/AKT/NF-B axis was able to prevent aberrant bone formation and attenuate cartilage degeneration in OA mice.
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