Pharmacological inhibition of S6K1 impairs self‐renewal and osteogenic differentiation of bone marrow stromal cells. Issue 1 (28th August 2017)

• Record Type: Journal Article
• Authors: Gu, Xiaohui; Fu, Xuejie; Lu, Jihang; Saijilafu, ; Li, Bin; Luo, Zong‐ping; Chen, Jianquan
• Is Part Of: Journal of cellular biochemistry. Volume 119:Issue 1(2018)
• Page Start: 1041
• Page End: 1049
• Publication Date: 2017-08-28
• Subjects: BMSCs -- LY2584702 -- osteogenic differentiation -- S6K1 -- self‐renewal; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.26272
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: mTORC1 signaling not only plays important physiological roles in the regulation of proliferation and osteogenic differentiation of BMSCs, but also mediates exogenous Wnt‐induced protein anabolism and osteoblast differentiation. However, the downstream effectors of the mTORC1 signaling in the above processes are still poorly understood. In this study, we explored the specific role of S6K1, one of the major targets of the mTORC1 pathway, in BMSCs self‐ renewal and osteogenic differentiation. We first found that S6K1 was active in primary mouse bone marrow stromal cells, and further activated upon osteogenic induction. We then determined the effects of S6K1 inhibition by LY2584702 Tosylate, a selective inhibitor of S6K1 (hereafter S6KI), using both primary mouse bone marrow stromal cells and ST2 cells. Colony‐Forming Unit‐Fibroblast (CFU‐F) assays showed that S6KI dramatically reduced the total number of colonies formed in primary BMSCs cultures. Under the basal osteogenic culture condition, S6KI significantly inhibited mRNA expression of osteoblast marker genes ( Sp7, Bglap, Ibsp, and Col1a1 ), ALP activity and matrix mineralization. Upon Wnt3a treatments, S6KI inhibited Wnt3a‐induced osteoblast differentiation and expression of protein anabolism genes in ST2 cells, but to a much lesser degree than rapamycin (a specific inhibitor of mTORC1 signaling). Collectively, our findings have demonstrated that pharmacological inhibition of S6K1 impaired self‐ renewal and osteogenic differentiation of BMSCs, but only partially suppressed exogenous Wnt3a‐induced osteoblast differentiation and protein anabolism. Abstract : Our findings have demonstrated that pharmacological inhibition of S6K1 impaired self renewal and osteogenic differentiation of BMSCs, but only partially suppressed exogenous Wnt3a‐induced osteoblast differentiation and protein anabolism.