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Trim21 deficiency alleviates osteoporosis by inhibiting osteoclast differentiation through regulating Txnip
Ya-Chen Peng1, Yong-Sheng Ye1,2, Qin-Xiao Hu1
1Department of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University, Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, Guangdong, 510630, People's Republic of China.
Objective:
The tripartite motif containing 21 (Trim21), an E3 ubiquitin ligase, plays a crucial role in the progression of various skeletal diseases, particularly in osteoporosis. In our previous study, Trim21 deficiency was shown to exert dual effects by suppressing bone resorption and enhancing osteogenesis. However, the specific mechanism by which Trim21 inhibits osteoclast (OC) differentiation remains unclear. In this study, we utilized a myeloid cell-specific conditional knockout model of Trim21 to investigate the underlying regulatory mechanisms.
Methods:
OC-specific Trim21 knockout mice were generated and subjected to ovariectomy (OVX) to establish a model of postmenopausal osteoporosis. Bone mass and OC activity were then evaluated using micro-computed tomography (micro-CT) and tartrate-resistant acid phosphatase (TRAP) staining. Bone marrow-derived macrophages (BMMs) were induced to differentiate into OCs, and gene expression levels were detected by qRT-PCR. Additionally, proteomic analysis was performed to identify downstream regulatory proteins influenced by Trim21.
Results:
OC-specific Trim21 deletion alleviated OVX-induced bone loss by inhibiting bone resorption and preserving bone mass. Myeloid-specific Trim21 deletion impaired OC differentiation and suppressed the expression of key OC markers. Thioredoxin-interacting protein (Txnip), was identified as a downstream effector regulated by Trim21.
Conclusion:
Trim21 deletion attenuates osteoporosis-induced bone loss, likely by suppressing osteoclast differentiation through modulation of Txnip, thereby presenting a potential novel therapeutic target for osteoporosis treatment.
Insights
Tripartite motif containing 21 (Trim21) deficiency protects against osteoporosis by inhibiting osteoclast differentiation. This mechanism involves the downstream effector Thioredoxin-interacting protein (Txnip), offering a potential therapeutic target.
Area of Science:
- Skeletal Biology
- Molecular Endocrinology
- Osteoporosis Research
Background:
- Tripartite motif containing 21 (Trim21) is an E3 ubiquitin ligase implicated in skeletal diseases like osteoporosis.
- Previous studies indicated Trim21 deficiency has dual effects: suppressing bone resorption and enhancing osteogenesis.
- The precise mechanism by which Trim21 influences osteoclast (OC) differentiation requires elucidation.
Purpose of the Study:
- To investigate the regulatory mechanisms of Trim21 in osteoclast differentiation using a myeloid cell-specific conditional knockout model.
- To understand how Trim21 deficiency impacts bone mass and OC activity in a postmenopausal osteoporosis model.
Main Methods:
- Generation of OC-specific Trim21 knockout mice and establishment of an ovariectomy (OVX)-induced osteoporosis model.
- Evaluation of bone mass and OC activity via micro-computed tomography (micro-CT) and TRAP staining.
- Assessment of gene expression in BMMs-derived OCs using qRT-PCR and proteomic analysis to identify downstream targets.
Main Results:
- OC-specific Trim21 deletion significantly reduced OVX-induced bone loss by inhibiting bone resorption.
- Deletion of Trim21 in myeloid cells impaired OC differentiation and downregulated key OC markers.
- Thioredoxin-interacting protein (Txnip) was identified as a critical downstream protein regulated by Trim21.
Conclusions:
- Trim21 deletion attenuates osteoporosis by suppressing osteoclast differentiation.
- Modulation of Txnip by Trim21 is a key mechanism underlying its anti-osteoporosis effect.
- Targeting Trim21 and its downstream effector Txnip presents a potential therapeutic strategy for osteoporosis.
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