Stat3 loss in mesenchymal progenitors causes Job syndrome–like skeletal defects by reducing Wnt/β-catenin signaling
Stat3 loss in mesenchymal progenitors causes Job syndrome–like skeletal defects by reducing Wnt/β-catenin signaling
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DOI：
10.1073/pnas.2020100118
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发表时间：
2021-06
期刊：
影响因子：
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通讯作者：
P. S. Yadav;Shuhao Feng;Qian Cong;Hanjun Kim;Yuchen Liu;Yingzi Yang
中科院分区：
文献类型：
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作者：
P. S. Yadav;Shuhao Feng;Qian Cong;Hanjun Kim;Yuchen Liu;Yingzi Yang
意义了解罕见遗传病的细胞起源和分子机制不仅对罕见遗传病而且对相关常见疾病的人类生物学和病理学提供了宝贵的见解。常染色体显性遗传性高免疫球蛋白-E综合征(AD-HIEs)或工作综合征是一种因STAT3基因突变而导致骨骼缺陷的遗传病。我们已经通过使用细胞特异性Cre系删除STAT3来模拟作业综合症中的骨骼异常。我们发现，通过维持Wnt/β-catenin信号通路，成骨细胞系细胞中的STAT3是骨骼发育所必需的。STAT3基因缺失导致成骨细胞分化受损，原因是Wnt/β-catenin信号转导减少，SOST表达上调。我们的工作为进一步理解STAT3调控骨形成和维持的原理提供了基础。JOB综合征是一种罕见的遗传性疾病，由STAT3基因突变引起，主要特征是免疫功能障碍，并伴有骨骼发育异常，包括骨量减少、复发性长骨骨折和脊柱侧弯。到目前为止，对约伯综合征的骨缺陷尚无确切的治疗方法，治疗仅限于临床症状的处理。在这里，我们研究了STAT3调控骨骼发育和成骨细胞分化的分子机制。我们发现，在小鼠发育中的肢体间充质或骨祖细胞中去除STAT3功能会导致四肢变短，并伴有长骨中的多发性骨折，类似于工作综合症中的骨骼症状。然而，STAT3的缺失并没有改变胚胎发育过程中软骨细胞的分化和肥大，而成骨细胞的分化严重减少。全基因组转录组分析以及生化和组织学研究表明，STAT3缺失导致Wnt/β-catenin信号下调。通过注射β的小分子抑制剂BIO或与LRP5功能获得等位基因杂交来恢复WNT/STAT3-catenin信号通路，在很大程度上挽救了STAT3丢失所致的骨减少表型。这些研究揭示了STAT3在维持早期间充质细胞或骨祖细胞Wnt/β-catenin信号转导中的重要功能，并提供了证据表明，作业综合征中的骨缺陷可能是由于STAT3在骨发育过程中活性降低而导致Wnt/β-catenin信号减少所致。增强Wnt/β-连环蛋白信号转导通路可能是改善JOB综合征患者骨症状的一种治疗方法。
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. Job syndrome is a rare genetic disorder caused by STAT3 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 Stat3 regulates skeletal development and osteoblast differentiation. We showed that removing Stat3 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, Stat3 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 Stat3 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 Lrp5 gain of function (GOF) allele, rescued the bone reduction phenotypes due to Stat3 loss to a great extent. These studies uncover the essential functions of Stat3 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.