byEhime University

Dnmt1 regulates energy metabolism to ensure proper chondrocyte maturation and normal bone elongation. Credit: Taro Kuroda (ADRES, Ehime University)

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 has remained unclear.

In a new studypublishedinNature Communications, researchers from Ehime University investigated the function of Dnmt1 in bone growth. Using the musculoskeletal database "MSK-KP," they identified a strong association betweengenetic variationin DNMT1 and human height.

To examine its biological role, the team 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, the researchers performed RNA sequencing and DNA methylation analysis of cartilage from mutant and control mice. These experiments revealed that Dnmt1 directly regulates genes involved incellular energy metabolism. Indeed, chondrocytes frommutant miceshowed enhancedmetabolic 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.

More information: Yuta Yanagihara et al, Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes, Nature Communications (2025). DOI: 10.1038/s41467-025-65145-9 Journal information: Nature Communications

Provided by Ehime University