Institute of Musculoskeletal Medicine (IMM)
Regulation of bone metabolism by ADAR2-mediated RNA editing in bone marrow adipocytes
- Institute:
- Institute of Musculoskeletal Medicine (IMM)
- Subject area:
- Metabolic bone health
- Number of open position:
- 1
- Project title:
- Regulation of bone metabolism by ADAR2-mediated RNA editing in bone marrow adipocytes
- Project time:
- Full Docotoral Study-Model: 48 months
- Language requirements:
- Fluent written and spoken English, including the ability to write scientific English.
- Academic requirements:
- Master's degree (or equivalent) and hands-on laboratory experience in standard cell and molecular biology methods.
Project description:
Bone remodeling is orchestrated by bone-forming osteoblasts, metabolically active osteocytes, and matrix-resorbing osteoclasts. Emerging research highlights the role of bone marrow adipocytes (BMAds) in this process. Disruption of the balance between bone formation and resorption leads to metabolic bone diseases such as osteoporosis, characterized by reduced bone mass and increased fracture risk. Estrogen is crucial for maintaining bone health, suppressing osteoclast activity while promoting osteoblast function. Postmenopausal estrogen deficiency or therapeutic inhibition of estrogen signaling, such as with aromatase inhibitors in breast cancer therapy, drives BMAd expansion, exacerbating bone loss by enhancing osteoclast activity.
This project investigates the role of adenosine deaminases acting on RNA-2 (ADAR2), an RNA-editing enzyme, in regulating BMAd differentiation and its downstream effects on bone remodeling. ADAR2 mediates adenosine-to-inosine (A-to-I) RNA editing, which modulates mRNA functionality and cellular activity. Our preliminary findings show that estrogen deficiency increases ADAR2 expression during BMAd differentiation, enhancing RNA editing of calcium channel subunits GRIA2/3 (glutamate ionotropic receptor AMPA type subunits 2 and 3). This editing renders the channels calcium-impermeable, suppressing calcium influx, and promoting adipocyte differentiation. ADAR2 inhibition reversed these effects, restoring calcium signaling and attenuating BMAd differentiation.
In vivo, estrogen deficiency induced by ovariectomy in mice increased BMAd accumulation and bone loss. In vitro, estrogen inhibition with anastrozole increased ADAR2 expression and GRIA2/3 editing, promoting BMAd differentiation. Notably, ADAR2 silencing reversed these effects. Conditioned medium from estrogen-deficient BMAds enhanced osteoclast differentiation compared to controls. Silencing ADAR2 in BMAds reduced RANKL expression and decreased the RANKL/OPG ratio, emphasizing the dual role of ADAR2 in promoting BMAd differentiation and osteoclast activity.
The objectives of this project are to (I) elucidate how estrogen regulates ADAR2-GRIA2/3 signaling in BMAd differentiation, (II) characterize the role of ADAR2 in BMAd-mediated osteoclast activation, and (III) determine the contribution of ADAR2 to bone loss in sexual hormone-deficient conditions. This original and innovative research advances our understanding of ADAR2-mediated RNA editing in BMAd biology and its implications for bone remodeling, potentially unveiling new therapeutic targets for metabolic bone disorders.
To applicants: Please send following initial application documents to LMU-CSC Office before 7th December:
- Resume and Research Motivation Letter
- Certificate of Proficiency in English, equivalent to IELTS Test Academic 6.5 (no module below 6) or TOEFL IBT 95, is required
- Two letters of recommendation directly sent from your current Supervisors/Professors to LMU-CSC Office