Suppression of Nkx3.2 by phosphatidylinositol-3-kinase signaling regulates cartilage development by modulating chondrocyte hypertrophy

Abstract

Phosphatidylinositol-3-kinase (PI3K) is a key regulator of diverse biological processes including cell proliferation, migration, survival, and differentiation. While a role of PI3K in chondrocyte differentiation has been suggested, its precise mechanisms of action are poorly understood. Here we show that PI3K signaling can down-regulate Nkx3.2 at both mRNA and protein levels in various chondrocyte cultures in vitro. In addition, we have intriguingly found that p85β, not p85α, is specifically employed as a regulatory subunit for PI3K-mediated Nkx3.2 suppression. Furthermore, we found that regulation of Nkx3.2 by PI3K requires Rac1–PAK1, but not Akt, signaling downstream of PI3K. Finally, using embryonic limb bud cultures, ex vivo long bone cultures, and p85β knockout mice, we demonstrated that PI3K-mediated suppression of Nkx3.2 in chondrocytes plays a role in the control of cartilage hypertrophy during skeletal development in vertebrates.

Cordycepin inhibits chondrocyte hypertrophy of mesenchymal stem cells through PI3K/Bapx1 and Notch signaling pathway

“…Bapx1 can suppress chondrocyte hypertrophy in ATDC5 cells (34). PI3K-mediated suppression of Bapx1 in chondrocytes also plays a role in the control of cartilage hypertrophy during skeletal development in vertebrates (35). It is well known that FAK activates multiple integrin-mediated signal transduction pathways such as PI3K/Akt pathway (36).…”

Cartilage-Specific and Cre-Dependent Nkx3.2 Overexpression In Vivo Causes Skeletal Dwarfism by Delaying Cartilage Hypertrophy

“…In particular, Nkx3.2 is initially expressed in chondrogenic precursor cells, and later during cartilage maturation, expression is restricted to proliferating chondrocytes (Murtaugh et al, ). Furthermore, multiple in vitro studies have suggested that Nkx3.2 promotes chondrogenic differentiation, delays chondrocyte hypertrophy, and inhibits chondrocyte apoptosis (Murtaugh et al, ; Zeng et al, ; Kim et al, ; Provot et al, ; Park et al, ; Choi et al, ; Kawato et al, ; Kim et al, ).…”

A post-translational modification cascade employing HDAC9-PIASy-RNF4 axis regulates chondrocyte hypertrophy by modulating Nkx3.2 protein stability

“…While we and others have shown diverse functions of Nkx3.2 during cartilage development, it remains poorly understood how Nkx3.2 can be regulated. Although we previously demonstrated that Nkx3.2 protein stability can be regulated by the Ihh-Wnt5a axis [10] and also by phosphatidylinositol-3-kinase signaling [53], both of which engage downstream effectors that modulate Nkx3.2 ubiquitination via phosphorylation. Furthermore, these effectors (i.e., CK2 and PAK1) are not expressed in a stage-specific manner during chondrogenesis.…”