Inhibition of STAT5A promotes osteogenesis by DLX5 regulation

Cell Death Dis. 2018 Nov 14;9(11):1136. doi: 10.1038/s41419-018-1184-7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / genetics
  • Cell Differentiation
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Femur / injuries
  • Femur / metabolism
  • Fracture Healing / genetics
  • Fractures, Bone / genetics*
  • Fractures, Bone / metabolism
  • Fractures, Bone / pathology
  • Fractures, Bone / therapy
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Integrin-Binding Sialoprotein / genetics
  • Integrin-Binding Sialoprotein / metabolism
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Knockout
  • Osteoblasts / cytology
  • Osteoblasts / metabolism*
  • Osteogenesis / genetics*
  • Osteoporosis / genetics*
  • Osteoporosis / metabolism
  • Osteoporosis / pathology
  • Osteoporosis / prevention & control
  • Primary Cell Culture
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • STAT5 Transcription Factor / antagonists & inhibitors
  • STAT5 Transcription Factor / genetics*
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Core Binding Factor Alpha 1 Subunit
  • DLX5 protein, human
  • Homeodomain Proteins
  • Integrin-Binding Sialoprotein
  • RNA, Small Interfering
  • RUNX2 protein, human
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins