期刊
BIOLOGICAL CHEMISTRY
卷 399, 期 11, 页码 1313-1323出版社
WALTER DE GRUYTER GMBH
DOI: 10.1515/hsz-2018-0253
关键词
bone defect healing; bone marrow stromal cells; hypoxia; JAK2/STAT3 signaling; osteogenic differentiation
资金
- National Natural Science Foundation of China [81470718, 81470724, 81100736, 81771051]
- Guangzhou Education Bureau [1201610458]
- Guangzhou Science Technology and Innovation Commission [201704030024]
- Department of Science and Technology of Guangdong Province [2015B09092002]
- National Key Research and Development Program of China [2016YFC1102900, 2016YFC1102902]
- Zhejiang Provincial Natural Science Foundation of China [Y17H140023]
Mesenchymal stem cells (MSCs) undergo osteogenic differentiation during bone defect healing. However, the role of JAK2/STAT3 in the osteogenic differentiation of MSCs and bone defect healing is still not fully understood. In this study, we aimed to analyze the effect of AG490, a JAK2-specific inhibitor, on MSCs proliferation and osteogenic differentiation as well as in bone defect healing. We used AG490 to inhibit the JAK2/STAT3 signaling in a mice bone marrow stromal cells (BMSCs) culture. AG490 inhibited BMSCs proliferation and osteogenic differentiation markers, i.e. Colla, Alp and Ocn expression in mRNA and protein levels. Inhibition of JAK2 reduced ALP activity and matrix mineralization in BMSCs culture. Inhibition of JAK2 reduced phosphorylation of STAT3, AKT, P38, and JNK phosphorylation. Immunohistochemistry showed high numbers of pJAK2, pSTAT3 and ALP positive cells and AG490 reduced this effect in vivo. Histology and Lt-computed tomography (CT) data showed that AG490 treatment inhibits bone regeneration and bone defect healing. Our results clearly showed the inhibitory effect of AG490 on proliferation and osteogenic differentiation of BMSCs, bone regeneration and bone defect healing. Moreover, AG490 inhibited phosphorylation of STAT3, P38, JNK and AKT. This suggests the possible role of JAK2/STAT3 signaling in hypoxia-induced osteogenic differentiation of MSCs and bone defect healing.
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