期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 31, 期 8, 页码 1617-1630出版社
WILEY
DOI: 10.1002/jbmr.2819
关键词
OSTEOBLAST; BONE DEVELOPMENT; SMAD; PI3K; BMP
资金
- MEC [BFU2011-24254, BFU 2014-56313]
- Fundacio La Marato de TV3
- ISCIII [RETIC RD06/0020]
Bone formation and homeostasis is carried out by osteoblasts, whose differentiation and activity are regulated by osteogenic signaling networks. A central mediator of these inputs is the lipid kinase phosphatidylinositol 3-kinase (PI3K). However, at present, there are no data on the specific role of distinct class IA PI3K isoforms in bone biology. Here, we performed osteoblast-specific deletion in mice to show that both p110 alpha and p110 beta isoforms are required for survival and differentiation and function of osteoblasts and thereby control bone formation and postnatal homeostasis. Impaired osteogenesis arises from increased GSK3 activity and a depletion of SMAD1 protein levels in PI3K-deficient osteoblasts. Accordingly, pharmacological inhibition of GSK3 activity or ectopic expression of SMAD1 or SMAD5 normalizes bone morphogenetic protein (BMP) transduction and osteoblast differentiation. Together, these results identify the PI3K-GSK3-SMAD1 axis as a central node integrating multiple signaling networks that govern bone formation and homeostasis. (C 2016 American Society for Bone and Mineral Research.
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