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miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2
Jing Y Krzeszinski1, Wei Wei1, HoangDinh Huynh1
1Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Abstract:
Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.
Insights
MicroRNAs regulate bone health. This study identifies miR-34a as a key suppressor of osteoclast formation, reducing bone loss in osteoporosis and cancer bone metastasis, offering therapeutic potential.
Area of Science:
- Skeletal Biology
- Molecular Biology
- Oncology
Background:
- Osteoclasts drive bone resorption in osteoporosis and cancer metastasis.
- MicroRNAs are crucial regulators of physiological and pathological processes.
- The role of microRNAs in skeletal biology, particularly osteoclastogenesis, remains incompletely understood.
Purpose of the Study:
- To identify novel microRNAs regulating osteoclast differentiation and function.
- To investigate the therapeutic potential of microRNAs in skeletal diseases and bone metastasis.
Main Methods:
- Analysis of miR-34a expression during osteoclast differentiation.
- Generation and analysis of miR-34a-overexpressing and knockout mouse models.
- Assessment of bone mass and resorption in mouse models of osteoporosis and cancer metastasis.
- Pharmacological intervention using miR-34a nanoparticles.
- Identification of direct miR-34a targets using molecular assays.
Main Results:
- miR-34a is downregulated during osteoclast differentiation and acts as a critical suppressor of osteoclastogenesis and bone resorption.
- miR-34a overexpression in osteoclasts reduces bone resorption and increases bone mass.
- miR-34a deficiency exacerbates bone loss in osteoporosis and promotes bone metastasis of breast and skin cancers.
- miR-34a nanoparticle treatment effectively attenuates osteoporosis and cancer bone metastasis.
- Transforming growth factor-β-induced factor 2 (Tgif2) is identified as a direct pro-osteoclastogenic target of miR-34a.
Conclusions:
- miR-34a is a key suppressor of osteoclast activity and bone resorption.
- miR-34a represents a promising therapeutic target for skeletal protection and mitigating cancer bone metastasis.
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