STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis
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Updated: Oct 12, 2025
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Siru Zhou1, Qinggang Dai2, Xiangru Huang1
1Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Science, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Disease, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
Abstract:
Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.
Insights
Signal transducer and activator of transcription 3 (STAT3) mutations cause skeletal deformities in AD-HIES. STAT3 in osteoblasts is crucial for bone development and homeostasis, offering a potential therapeutic target.
Area of Science:
- Genetics and Molecular Biology
- Skeletal Biology
- Developmental Biology
Background:
- Autosomal dominant–hypomorphic interleukin-21 receptor signaling pathway mutations (AD-HIES) often manifest as skeletal deformities.
- Heterozygous loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3) are the primary cause of AD-HIES.
- The precise mechanisms underlying STAT3-related skeletal defects and available treatments remain limited.
Purpose of the Study:
- To investigate the role of STAT3 in osteoblasts versus osteoclasts in skeletal development.
- To elucidate the molecular mechanisms by which STAT3 influences osteoblast differentiation and bone homeostasis.
- To evaluate STAT3 as a potential therapeutic target for AD-HIES skeletal manifestations.
Main Methods:
- Generation of mice with osteoblast-specific or osteoclast-specific Stat3 deletion.
- Phenotypic analysis of skeletal deformities, including craniofacial structure, bone density, and fracture incidence.
- Molecular analyses to determine the interaction of STAT3 with transcription factors like MSX1 and its effect on downstream targets such as DLX5.
Main Results:
- Osteoblast-specific Stat3 deletion in mice recapitulated AD-HIES-like skeletal defects, including craniofacial malformations, osteoporosis, and fractures.
- STAT3, in conjunction with MSX1, was found to promote osteoblast differentiation by enhancing DLX5 transcription.
- Pharmacological activation of STAT3 partially ameliorated skeletal deformities in heterozygous knockout mice, whereas STAT3 inhibition exacerbated bone loss.
Conclusions:
- STAT3 plays a critical role in osteoblast differentiation and is essential for maintaining skeletal development and bone homeostasis.
- The STAT3-MSX1-DLX5 pathway is a key regulator of osteogenesis.
- Targeting STAT3 activation represents a promising therapeutic strategy for treating skeletal abnormalities in AD-HIES.
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