| First Author | Wu X | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 15 | Pages | 13512-21 |
| PubMed ID | 21324896 | Mgi Jnum | J:171139 |
| Mgi Id | MGI:4948785 | Doi | 10.1074/jbc.M110.187351 |
| Citation | Wu X, et al. (2011) p85{alpha} Regulates Osteoblast Differentiation by Cross-talking with the MAPK Pathway. J Biol Chem 286(15):13512-21 |
| abstractText | Class IA phosphoinositide 3-kinase (PI3K) is involved in regulating many cellular functions including cell growth, proliferation, cell survival, and differentiation. The p85 regulatory subunit is a critical component of the PI3K signaling pathway. Mesenchymal stem cells (MSC) are multipotent cells that can be differentiated into osteoblasts (OBs), adipocytes, and chondrocytes under defined culture conditions. To determine whether p85alpha subunit of PI3K affects biological functions of MSCs, bone marrow-derived wild type (WT) and p85alpha-deficient (p85alpha(-/-)) cells were employed in this study. Increased cell growth, higher proliferation rate and reduced number of senescent cells were observed in MSCs lacking p85alpha compare with WT MSCs as evaluated by CFU-F assay, thymidine incorporation assay, and beta-galactosidase staining, respectively. These functional changes are associated with the increased cell cycle, increased expression of cyclin D, cyclin E, and reduced expression of p16 and p19 in p85alpha(-/-) MSCs. In addition, a time-dependent reduction in alkaline phosphatase (ALP) activity and osteocalcin mRNA expression was observed in p85alpha(-/-) MSCs compared with WT MSCs, suggesting impaired osteoblast differentiation due to p85alpha deficiency in MSCs. The impaired p85alpha(-/-) osteoblast differentiation was associated with increased activation of Akt and MAPK. Importantly, bone morphogenic protein 2 (BMP2) was able to intensify the differentiation of osteoblasts derived from WT MSCs, whereas this process was significantly impaired as a result of p85alpha deficiency. Addition of LY294002, a PI3K inhibitor, did not alter the differentiation of osteoblasts in either genotype. However, application of PD98059, a Mek/MAPK inhibitor, significantly enhanced osteoblast differentiation in WT and p85alpha(-/-) MSCs. These results suggest that p85alpha plays an essential role in osteoblast differentiation from MSCs by repressing the activation of MAPK pathway. |
