Ulici Veronica, Hoenselaar Katie D, Gillespie J Ryan, Beier Frank
CIHR Group in Skeletal Development and Remodeling, Department of Physiology & Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada.
BMC Dev Biol. 2008 Apr 11;8:40. doi: 10.1186/1471-213X-8-40.
The majority of our bones develop through the process of endochondral ossification that involves chondrocyte proliferation and hypertrophic differentiation in the cartilage growth plate. A large number of growth factors and hormones have been implicated in the regulation of growth plate biology, however, less is known about the intracellular signaling pathways involved. PI3K/Akt has been identified as a major regulator of cellular proliferation, differentiation and death in multiple cell types.
Employing an organ culture system of embryonic mouse tibiae and LY294002, a pharmacological inhibitor of PI3K, we show that inhibition of the pathway results in significant growth reduction, demonstrating that PI3K is required for normal endochondral bone growth in vitro. PI3K inhibition reduces the length of the proliferating and particularly of the hypertrophic zone. Studies with organ cultures and primary chondrocytes in micromass culture show delayed hypertrophic differentiation of chondrocytes and increased apoptosis in the presence of LY294002. Surprisingly, PI3K inhibition had no strong effect on IGF1-induced bone growth, but partially blocked the anabolic effects of C-type natriuretic peptide.
Our data demonstrate an essential role of PI3K signaling in chondrocyte differentiation and as a consequence of this, in the endochondral bone growth process.
我们大多数骨骼通过软骨内成骨过程发育，该过程涉及软骨生长板中的软骨细胞增殖和肥大分化。大量生长因子和激素参与生长板生物学的调节，然而，对于其中涉及的细胞内信号通路了解较少。PI3K/Akt已被确定为多种细胞类型中细胞增殖、分化和死亡的主要调节因子。
利用胚胎小鼠胫骨器官培养系统和PI3K的药理抑制剂LY294002，我们发现抑制该信号通路会导致显著的生长减缓，表明PI3K是体外正常软骨内骨生长所必需的。PI3K抑制会缩短增殖区尤其是肥大区的长度。对器官培养物和微团培养中的原代软骨细胞的研究表明，在LY294002存在的情况下，软骨细胞肥大分化延迟且凋亡增加。令人惊讶的是，PI3K抑制对IGF1诱导的骨生长没有强烈影响，但部分阻断了C型利钠肽的合成代谢作用。
我们的数据证明PI3K信号在软骨细胞分化中以及由此在软骨内骨生长过程中起着至关重要的作用。
