A new mechanism and therapeutic target for craniofacial bone malformations associated with high IgE syndrome
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A new mechanism and therapeutic target for craniofacial bone malformations associated with high IgE syndrome.
A new mechanism and therapeutic target for craniofacial bone malformations associated with high IgE syndrome.
Autosomal Dominant High IgE Syndrome ( AD-HIES ) , also known as Job’s Syndrome, is a rare genetic disease mainly caused by a dominant negative mutation of STAT 3.
It is mainly characterized by multiple system immune function defects and abnormal bone development , Including osteoporosis, multiple spontaneous fractures, etc.
In addition, patients have a high incidence of cranio-maxillofacial developmental deformities, such as facial asymmetry, protruding forehead, retained deciduous teeth, impacted permanent teeth, premature craniofacial closure, tongue, mucosal and other abnormalities. Affect the survival and quality of life of patients [1] .
Previous research mainly focused on the mechanism of immune system disorders caused by STAT3 inactivation, but it is not clear how STAT3 inactivation causes bone deformities.
Some studies believe that AD-HIES-related bone deformities may be related to abnormal osteoclast activity, and try to treat them with anti-bone resorption drugs such as bisphosphonates, but the effect is not good.
Skeletal deformity is a typical clinical manifestation of AD-HIED, but there is still a lack of effective treatment methods.
Recently, Nature Communications published online research work STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis by Jiang Lingyong Group, School of Stomatology, Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine .
This study established an animal model of AD-HIES-related cranio-maxillofacial bone malformations, and demonstrated for the first time the molecular mechanism of AD-HIES-related skeletal malformations caused by osteoblast STAT3 inactivation by inhibiting Dlx5 transcription and reducing osteogenic activity; found and identified As a regulatory target of bone development and bone homeostasis, STAT3 provides new ideas and targets for the treatment of AD-HIES bone malformations and other related bone metabolism diseases.
Previous studies have suggested that AD-HIES-related osteoporosis may be related to osteoclast activity. Therefore, the author first used Ctsk Cre to establish osteoclast-specific Stat3 knockout mice.
However, it was found that the osteoclast-inactivated STAT3 mice did not develop AD. -HIES-like skeletal deformities, and Micro-CT analysis shows increased bone mass (previous results have been published in The Journal of Biological Chemistry ) [2] .
Further using Prx1 Cre and Osx Cre to establish an osteoblast cell line STAT3 inactivated mice, it was found that the mice developed skull and jaw deformities, osteoporosis, spontaneous fractures and other skeletal deformities similar to the clinical symptoms of AD-HIES patients.
Bone lineage cells (not osteoclasts) STAT3 is the pathogenesis of AD-HIES-related skeletal deformities, providing new ideas and models for the further development of new clinical treatment methods.
The authors used histological and cytological analysis to show that inactivation of the osteoblast cell line STAT3 leads to HIES-related skeletal deformities by inhibiting osteogenic activity.
In the exploration of the mechanism, through transcriptome sequencing analysis, it was found that the expression of genes related to bone development, osteoblast differentiation, and mineralization were all down-regulated.
Among them, Dlx5, which is closely related to cranio-maxillofacial development, may be an important target gene of STAT3.
The authors further used molecular biology experiments such as dual luciferase reporter system, co-immunoprecipitation, and point mutations to confirm that STAT3 can cooperate with MSX1 to regulate Dlx5 transcription and osteoblast differentiation.
Clinically, AD-HIES syndrome is caused by heterozygous inactivating mutations of STAT3, that is, cells still retain part of STAT3 activity.
The authors found that osteoblast precursor cells Stat3 heterozygous knockout mice ( Stat3 fl/+ ; Osx-cre ) exhibited AD-HIES-like skeletal deformities such as cranio-maxillofacial bone developmental malformations and bone quality on the basis of reduced STAT3 expression levels. Porosity, etc. (but the dwarf phenotype of homozygous mice does not appear) .
Compared with homozygous mice, heterozygous mice can better simulate the active state of STAT3 in clinical AD-HIED patients, and can be used as a model for further exploration of clinical treatment methods.
The authors use this model to find that the STAT3 agonist Colivelin not only promotes the differentiation of heterozygous mouse osteoblasts in vitro, but also enhances the osteogenic activity and bone mass of heterozygous mice in vivo, which may become AD-HIES-related bones. Potential therapeutic targets for deformities.
On the basis of developmental biology, the author further established an inducible conditional knockout model ( Stat3 fl/fl ; Col1-creERT ) , and found that the inactivation of osteoblast STAT3 in adulthood can also inhibit the osteogenic activity of mice and lead to mice. Bone loss.
And STAT3 inhibitor AG490 can also reduce the osteogenic activity of adult mice and lead to osteoporosis.
In the tail suspension model, loss of mechanics leads to decreased osteogenic activity and osteoporosis in mice, while Colivelin can promote osteogenic activity and prevent bone loss caused by loss of mechanics.
These results indicate that in addition to regulating bone development, STAT3 is also an important regulator of bone homeostasis and bone metabolism, and has become a potential therapeutic target for related bone metabolism diseases.
In summary, the study established an animal model of AD-HIES-related skeletal deformities and discovered a new pathogenic mechanism; it was confirmed that STAT3, in addition to regulating bone development, is also an important regulator of bone homeostasis and bone metabolism.
Activating residual STAT3 activity to regulate bone metabolism has a potential role in the clinical treatment of AD-HIES-related skeletal deformities, and at the same time provides new therapeutic targets for other related bone metabolism diseases.
Jiang Lingyong, Department of Oral and Craniofacial , Orthodontic-Orthodontics Center, The Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine , is the corresponding author of this article. Attending physicians, doctoral students Huang Xiangru and Jin Anting.
Professor Jiang Lingyong is committed to the clinical and basic work of comprehensive orthodontic treatment of dental and maxillofacial deformities.
His research direction is the study of the mechanism of orthodontic stress regulating tooth movement-related alveolar bone reconstruction and the clinical and pathogenic mechanism of dental and maxillofacial deformities.
He has won the honorary titles of the 4th National Famous Doctor·Young Young Talent and Shanghai Outstanding Academic Leader.
The main research team of the research group welcomes young scientific research talents and post-doctors from home and abroad to join.
A new mechanism and therapeutic target for craniofacial bone malformations associated with high IgE syndrome.
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