<i>Stat3</i> loss in mesenchymal progenitors causes Job syndrome–like skeletal defects by reducing Wnt/β-catenin signaling

Abstract

Job syndrome is a rare genetic disorder caused by <i>STAT3</i> mutations and primarily characterized by immune dysfunction along with comorbid skeleton developmental abnormalities including osteopenia, recurrent fracture of long bones, and scoliosis. So far, there is no definitive cure for the skeletal defects in Job syndrome, and treatments are limited to management of clinical symptoms only. Here, we have investigated the molecular mechanism whereby <i>Stat3</i> regulates skeletal development and osteoblast differentiation. We showed that removing <i>Stat3</i> function in the developing limb mesenchyme or osteoprogenitor cells in mice resulted in shortened and bow limbs with multiple fractures in long bones that resembled the skeleton symptoms in the Job Syndrome. However, <i>Stat3</i> loss did not alter chondrocyte differentiation and hypertrophy in embryonic development, while osteoblast differentiation was severely reduced. Genome-wide transcriptome analyses as well as biochemical and histological studies showed that <i>Stat3</i> loss resulted in down-regulation of Wnt/β-catenin signaling. Restoration of Wnt/β-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, or crossing with a <i>Lrp5</i> gain of function (GOF) allele, rescued the bone reduction phenotypes due to <i>Stat3</i> loss to a great extent. These studies uncover the essential functions of <i>Stat3</i> in maintaining Wnt/β-catenin signaling in early mesenchymal or osteoprogenitor cells and provide evidence that bone defects in the Job Syndrome are likely caused by Wnt/β-catenin signaling reduction due to reduced STAT3 activities in bone development. Enhancing Wnt/β-catenin signaling could be a therapeutic approach to reduce bone symptoms of Job syndrome patients.