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Published on: July 3, 2020
Lysine methyltransferase methyltransferase-like 13 regulates bone marrow mesenchymal stem cells osteo-adipogenic
Ying Liu1, Ao Wang1, Ziwen Liu2
1Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Purpose:
Recent research indicates that the senescence of bone marrow mesenchymal stem cells (BMSCs) disrupts the osteo-adipogenic balance, a primary factor contributing to the development of osteoporosis. Our previous findings have implicated methyltransferases in this process, among which methyltransferase-like 13 (METTL13) has been established to regulate cell fate, although its role in osteoporosis has yet to be determined.
Methods:
Bone formation was assessed using micro-computed tomography and hematoxylin and eosin staining. Protein expression in bone tissues was examined immunohistochemically, and cellular mRNA and protein levels were determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. Cellular senescence was evaluated based on β-galactosidase staining, and osteogenic and adipogenic differentiation was examined using alkaline phosphatase, Alizarin Red S, and Oil Red O staining. Protein interactions and DNA binding were determined using co-immunoprecipitation and chromatin immunoprecipitation.
Results:
METTL13 expression was significantly enhanced in ovariectomy-induced senescent bone and BMSCs, whereas METTL13 knockdown markedly reversed etoposide-induced cellular senescence. By binding to forkhead box protein A1 (Foxa1), METTL13 promotes the preferential differentiation of BMSCs into adipocytes, as opposed to osteocytes. Moreover, Foxa1 had effects opposite to those of METTL13 on BMSC differentiation, inhibiting the nuclear entry of METTL13. Notably, blocking the nuclear import of Foxa1 suppressed the transcriptional expression of HES-1, which promoted the adipogenic differentiation of BMSCs and inhibited osteogenic differentiation.
Conclusions:
Our findings in this study revealed the mechanisms whereby METTL13 promotes BMSC senescence and disrupts BMSC differentiation, on the basis of which, we identified the METTL13-Foxa1-HES-1 axis as a potential therapeutic target for treatment of osteoporosis.
Insights
Methyltransferase-like 13 (METTL13) promotes bone marrow mesenchymal stem cell (BMSC) senescence and disrupts their differentiation, contributing to osteoporosis. Targeting the METTL13-Foxa1-HES-1 pathway may offer a novel therapeutic strategy for osteoporosis.
Area of Science:
- Stem cell biology
- Molecular mechanisms of aging
- Bone biology
Background:
- Senescence of bone marrow mesenchymal stem cells (BMSCs) disrupts osteo-adipogenic balance, a key factor in osteoporosis development.
- Methyltransferases are implicated in BMSC senescence, with methyltransferase-like 13 (METTL13) known to regulate cell fate.
Purpose of the Study:
- To investigate the role of METTL13 in osteoporosis by examining its function in BMSC senescence and differentiation.
- To elucidate the molecular mechanisms underlying METTL13's effects on BMSC fate and its potential as a therapeutic target.
Main Methods:
- Assessed bone formation via micro-computed tomography and H&E staining.
- Quantified mRNA and protein levels using qRT-PCR and western blotting.
- Evaluated senescence and differentiation using specific staining (β-galactosidase, ALP, Alizarin Red S, Oil Red O).
- Determined protein interactions and DNA binding via co-immunoprecipitation and chromatin immunoprecipitation.
Main Results:
- METTL13 expression was elevated in senescent bone and BMSCs; METTL13 knockdown reversed senescence.
- METTL13 binds to Foxa1, promoting BMSC adipogenic differentiation over osteogenic differentiation.
- Foxa1 antagonized METTL13's effects by inhibiting its nuclear entry, suppressing HES-1 expression and promoting adipogenesis.
Conclusions:
- METTL13 promotes BMSC senescence and disrupts differentiation through the METTL13-Foxa1-HES-1 axis.
- This axis represents a potential therapeutic target for osteoporosis treatment.
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