<i>Stat3</i> loss in mesenchymal progenitors causes Job syndrome–like skeletal defects by reducing Wnt/β-catenin signaling
Prem Swaroop Yadav, Shuhao Feng, Qian Cong, Hanjun Kim, Yuchen Liu, Yingzi Yang
Abstract
Significance Understanding the cell origin and molecular mechanisms underlying rare genetic diseases provides invaluable insights into human biology and pathology of not only rare genetic diseases but also related common disorders. Autosomal dominant hyper immunoglobulin-E syndrome (AD-HIES) or Job syndrome is a genetic disease with skeletal defects resulting from mutations in the STAT3 gene. We have modeled the skeletal abnormality in Job Syndrome by deleting Stat3 using cell-specific Cre lines. We found that Stat3 is required in osteoblast lineage cells for skeletal development by maintaining Wnt/β-catenin signaling. Deletion of Stat3 resulted in impaired osteoblast differentiation due to reduced Wnt/β-catenin signaling with upregulated Sost expression. Our work provides a foundation for further understanding the principles whereby Stat3 governs bone formation and maintenance.