The balance of nutrition in early childhood affects height.

We elucidated that DNA methyltransferase 1 (Dnmt1), an epigenetic regulator, properly controls bone elongation by modulating energy metabolism in growth plate chondrocytes. Epigenetic regulation is influenced by lifestyle factors and affects development and disease. Our study reveals that Dnmt1 determines long bone length through energy metabolic regulation, suggesting that nutritional cues may shape chondrocyte function and providing insights for preventing or treating growth disorders and osteoarthritis.

Chondrocytes play a crucial role in skeletal development. Many bones, such as those in the arms and legs, are formed through endochondral ossification, in which chondrocytes assemble to create a cartilage scaffold that is later replaced by bone. The maturation of chondrocytes, required for their diverse functions, is regulated by epigenetic mechanisms that modulate gene activity without altering DNA sequences. Among these, DNA methylation is especially important, serving as a switch to suppress gene expression. Maintenance of proper DNA methylation requires the enzyme DNA methyltransferase 1 (Dnmt1). However, the role of Dnmt1 in bone and cartilage remained unclear.
In this study, we investigated the function of Dnmt1 in bone growth. Using the musculoskeletal database “MSK-KP,” we identified a strong association between genetic variation in DNMT1 and human height. To examine its biological role, we generated mice lacking Dnmt1 specifically in mesenchymal progenitors of the limbs. These mutant mice displayed markedly shortened tibial length compared with controls. Detailed analysis revealed that Dnmt1 is expressed in the proliferative zone (PZ) of the growth plate cartilage, which is essential for longitudinal bone growth. Mutant mice showed reduced PZ, expanded hypertrophic zone (HZ), and accelerated calcification, indicating premature chondrocyte maturation.
To clarify the molecular basis, we performed RNA sequencing and DNA methylation analysis of cartilage from mutant and control mice. These experiments revealed that Dnmt1 directly regulates genes involved in cellular energy metabolism. Indeed, chondrocytes from mutant mice showed enhanced metabolic activity, and inhibition of metabolism suppressed the accelerated maturation phenotype. Furthermore, experiments using human chondrocytes isolated from surgical samples demonstrated similar results: reduction of Dnmt1 enhanced energy metabolism and increased markers of chondrocyte maturation, such as osteocalcin.
Taken together, these findings reveal that Dnmt1 regulates energy metabolism to ensure proper chondrocyte maturation and normal bone elongation. This discovery highlights the potential of nutritional and metabolic interventions in the prevention and treatment of impaired bone growth and osteoarthritis.

Reference URL: https://www.nature.com/articles/s41467-025-65145-9

Bibliographic Information

Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes,
Yuta Yanagihara, Masatomo Takahashi, Yoshihiro Izumi, Tomofumi Kinoshita, Masaki Takao, Takeshi Bamba, Yuuki Imai.
Nat Commun 16, 9492 (2025).
https://doi.org/10.1038/s41467-025-65145-9

Fundings

• The Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Number: JP20K18066, JP24K19584, JP23689066, JP15H04961, JP19H03786, and JP22H03203.)
• The Research Support Project for Life Science and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (Grant Number: JP24ama121055)
• The MEXT Cooperative Research Project Program, Medical Research Center Initiative for High Depth Omics, and Coalition of Universities for Research Excellence Program (CURE): JPMXP1323015486 for the Medical Institute of Bioregulation (MIB), Kyushu University

Media

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  Dnmt1 regulates energy metabolism to ensure proper chondrocyte maturation and normal bone elongation.

  Loss of Dnmt1 disrupted normal DNA methylation in chondrocytes, leading to increased expression of genes involved in cellular energy metabolism. As a result, metabolic abnormalities occurred, promoting the differentiation and calcification of growth plate chondrocytes and ultimately inhibiting bone growth. These findings suggest that proper maintenance of DNA methylation mediated by Dnmt1 during chondrocyte differentiation regulates intracellular energy metabolism through gene expression control, thereby maintaining the balance of chondrocyte differentiation and calcification and ensuring normal bone growth. [Illustrated by Taro Kuroda (ADRES, Ehime univ.)]

  credit : Yuta Yanagihara, Yuuki Imai, Ehime University
  Usage Restriction : Permission should be obtained.