Abstract
Previous studies have addressed the involvement of phosphoinositide-specifc phospholipase γ1 (PLCγ1) and protein kinase B (PKB/Akt) in osteoarthritis (OA) pathogenesis, but it is not ascertained the possibility of them to be potential targets for OA therapy. Here, through local intra-articular injection of PLCγ or Akt inhibitor in a rat OA model induced by anterior cruciate ligament transaction plus medial meniscus resection, the architecture of chondrocyte and matrix organization of articular cartilage were observed using histopathological assays and Aggrecan, Col2, PLCγ1, and Akt levels were detected using immunohistochemistry assays. By treatment of Akt or PLCγ inhibitor and transfection of different PLCγ1- or Akt-expressing vectors in rat OA model chondrocytes, Aggrecan, Col2, PLCγ1, p-PLCγ1, Akt, and p-Akt levels were detected using western blotting analysis. The binding between PLCγ1 and Akt was assessed with co-immunoprecipitation assays in human OA chondrocytes. These results showed that PLCγ inhibition protected chondrocytes against OA, but Akt inhibition did not dramatically aggravate OA progression. There were mutual antagonism and binding between PLCγ1 and Akt that could be regulated by their phosphorylation levels. Consequently, the data reveal that the inhibition of PLCγ1 may provide an attractive therapeutic target for OA therapy, implicating its binding to Akt.
Highlights
Osteoarthritis (OA) is a chronic and degenerative disease of articular cartilage, mainly characterized by chondrocyte death and articular cartilage matrix degradation in OA pathogenesis
We previously show that the activation of Akt contributed to the chondroprotection of nicotine, berberine, and morroniside on OA chondrocytes through promoting matrix synthesis, respectively [17,18,19]
Given the number of signal cascades triggered by activated Akt, which might make it difficult to understand its regulatory mechanism, the effect of Akt on articular cartilage was detected with the treatment of its pharmaceutical inhibitor Triciribine (TCN) in this study
Summary
Osteoarthritis (OA) is a chronic and degenerative disease of articular cartilage, mainly characterized by chondrocyte death and articular cartilage matrix degradation in OA pathogenesis. Either suppressing matrix degradation or promoting matrix synthesis could mitigate or prevent OA degeneration. Some signal molecules, such as p38, JNK and ERK MAP kinases, and PI-3 kinase/Akt, could regulate the expression levels of Aggrecan(a proteoglycan) and type II collagen (Col 2), which are main components in articular cartilage matrix, to suppress or promote matrix synthesis [1]. Local intra-articular injection of rapamycin(mTOR inhibitor) or cartilage-specific deletion of mTOR can delay articular cartilage degeneration in a murine model of OA or protect mice from osteoarthritis [3, 4]. Targeting the signal molecules involved in chondrocyte metabolism may be a potent solution for OA therapy
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