Abstract
The regulation of osteogenesis is important for bone formation and fracture healing. Despite advances in understanding the molecular mechanisms of osteogenesis, crucial modulators in this process are not well-characterized. Here we demonstrate that suppression of signal transducer and activator of transcription 5A (STAT5A) activates distal-less homeobox 5 (DLX5) in human bone marrow-derived stromal cells (hBMSCs) and enhances osteogenesis in vitro and in vivo. We show that STAT5A negatively regulates expression of Dlx5 in vitro and that STAT5A deletion results in increased trabecular and cortical bone mass and bone mineral density in mice. Additionally, STAT5A deletion prevents age-related bone loss. In a murine fracture model, STAT5A deletion was found to significantly enhance bone remodeling by stimulating the formation of a fracture callus. Our findings indicate that STAT5A inhibition enhances bone formation by promoting osteogenesis of BMSCs.
Highlights
Human bone marrow mesenchymal stromal cells may differentiate into osteoblasts, chondrocytes, adipocytes, or tenocytes depending on culture conditions
signal transducer and activator of transcription 5A (STAT5A) directly regulates distal-less homeobox 5 (DLX5) in Human bone marrow mesenchymal stromal cells (hBMSCs) To examine the relationship between STAT5A and the osteogenic transcriptional regulator DLX5 luciferase assays for each regulator were performed at day 5 after induction of osteogenesis in hBMSCs
Emerging evidence suggests that Janus-activated kinase (JAK)-signal transducers and activators of transcription (STAT) signaling plays an important role in osteoblast differentiation and bone formation[27,32,33]
Summary
Human bone marrow mesenchymal stromal cells (hBMSCs) may differentiate into osteoblasts, chondrocytes, adipocytes, or tenocytes depending on culture conditions. Osteoblast differentiation of hBMSCs is a well-characterized process and proceeds as a result of the timely expression of genes, such as alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), distal-less homeobox 5 (DLX5), osterix (OSX), and osteocalcin (OCN), followed by extracellular matrix synthesis and mineralization[1,2]. RUNX2 has been characterized as the master transcription factor in osteogenic differentiation and bone formation[3,4]. Members of the signal transducers and activators of transcription (STAT) family play important roles in cell proliferation, differentiation, and survival via effects on the expression of cytokines, growth factors, and hormones[8,9,10,11]. There are two isoforms of STAT5: Official journal of the Cell Death Differentiation Association
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