Abstract
BackgroundSignal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor that participates in various biologic processes. Loss of Stat3 causes hyperimmunoglobulin E syndrome, presenting with skeletal disorders including osteoporosis, recurrent fractures, scoliosis, and craniosynostosis. The objective of this study is to explore the effect and mechanism of Stat3 on osteogenesis of mesenchymal progenitors.MethodsStat3 was conditionally knockout (CKO) in mesenchymal progenitors by crossing the pair-related homeobox gene 1-cre (Prx1-Cre) with Stat3-floxed strain mice. Whole-mount-skeletal staining, histology, and micro-CT were used to assess the differences between Stat3 CKO and control mice. Further, in vitro experiments were conducted to evaluate the osteogenesis potential of primary isolated bone marrow mesenchymal stem cells (BMSCs) from both control and Stat3 CKO mice. After osteogenic induction for 14d, alizarin red staining was used to show the calcium deposit, while the western blotting was applied to detect the expression of osteogenic markers.ResultsCompared with the control, Stat3 CKO mice were present with shortened limbs, multiple fractures of long bone, and open calvarial fontanels. The abnormal growth plate structure and reduced collagen fiber were found in Stat3 CKO limbs. According to micro-CT analysis, the reduced cortical bone thickness and bone volume were found on Stat3 CKO mice. The in vitro osteogenic differentiation of BMSCs was inhibited in Stat3 CKO samples. After osteogenic induction for 14d, the significantly diminished calcium deposits were found in Stat3 CKO BMSCs. The decreased expression of osteogenic markers (OPN and COL1A1) was observed in Stat3 CKO BMSCs, compared with the control.ConclusionsStat3 played a critical role in bone development and osteogenesis. Loss of Stat3 impaired the osteogenesis of mesenchymal progenitors in vivo and in vitro.
Highlights
Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor that participates in various biologic processes
Stat3 disruption in osteoblasts and osteocytes significantly decreased bone strength and reduced load-driven bone formation [11]. These results suggested the important role of Stat3 in osteogenesis of osteoblastic cell lineages
Generation of Stat3 conditional knockout (CKO) mice To investigate the function of Stat3 in skeleton development, Stat3 was deleted in mesenchymal progenitors by use of Prx1-Cre
Summary
Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor that participates in various biologic processes. The skeleton development is a complex process involving cell migration, proliferation, and differentiation [1]. The differentiation of mesenchymal progenitors into osteoblasts is critical for both intramembranous and endochondral ossification [2]. Such process requires the participation of multiple signaling pathways. Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic transcription factor and extensively participates in cell proliferation and differentiation [3]. After tyrosine phosphorylation by cytokines and growth factors, Stat molecules dimerize and translocate into the nucleus and regulate gene transcription [4]
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