Mechanism by which RNA-modifying enzyme METTL5 supports bone formation elucidated: International collaborative research discovers antioxidant regulatory mechanism involved in bone formation abnormalities.

June 1, 2026
Kyushu Dental University (Public University Corporation)

An international collaborative research group, in which Professor Shoichiro Furukabu of the Division of Biochemistry at Kyushu Dental University (Campus: Kitakyushu City, Fukuoka Prefecture, President: Awano Shuji) is one of the corresponding authors, has revealed, together with Professor Quan Yuan and others from the West Huastoma Hospital, Sichuan University, China, that the RNA modifying enzyme METTL5 (*1) protects bone-forming cells from oxidative stress and supports normal bone formation. This finding may deepen our understanding of the pathogenesis of METTL5-related diseases and osteogenesis imperfecta, and could lead to the development of new therapies targeting antioxidant regulation. The results of this research were published in the international academic journal JCI Insight in the fields of medicine and life sciences on May 8, 2026.

[Key points of this research presentation]

• Mice lacking METTL5 are smaller in size and exhibit reduced bone mass and bone formation ability.
• METTL5 regulates the production of OSER1 (*2) protein, thereby maintaining the antioxidant function of osteoblasts (*3).
• METTL5 deficiency reduces the antioxidant capacity of osteoblasts, making them more vulnerable to oxidative stress.
• Administration of the antioxidant N-acetylcysteine ​​(NAC) (*4) partially improves bone malformations caused by METTL5 deficiency.

[About the Division of Biochemistry at Kyushu Dental University]

Founded in 1952, the organization restarted under its current structure in 2017. It is dedicated to unraveling the mechanisms by which cells, the smallest units of life, perform various biological functions.

[Research background]

　Bone is not a tissue that remains unchanged once formed; it is maintained throughout life through repeated formation and absorption. The normal functioning of osteoblasts and the mesenchymal stem cells (*5) from which they originate is essential for bone growth, maintenance of bone mass, and repair after fractures. On the other hand, the mechanism of bone formation is extremely complex, involving various factors such as genes, intracellular signaling, metabolism, and oxidative stress. In recent years, "RNA modification," in which RNA is chemically modified within cells, has attracted attention as an important mechanism for regulating gene expression and protein production.

  METTL5 is known as an enzyme that modifies ribosomal RNA (*6) with m6A (*7). Previous studies have reported that abnormalities in METTL5 are associated with diseases such as intellectual disability, microcephaly, facial deformities, and short stature. However, the detailed mechanism by which METTL5 abnormalities lead to skeletal formation and bone loss has not been fully clarified.

[Research content and results]

　An international collaborative research group, in which Professor Shoichiro Furukabu of the Division of Biochemistry at Kyushu Dental University is one of the corresponding authors, investigated the role of the RNA modifying enzyme METTL5 in bone formation.

First, we analyzed mice lacking METTL5 and found that they were smaller and had lower bone mass compared to normal mice. Further examination revealed that while there were no significant changes in bone-breaking cells, the function of osteoblasts (bone-forming cells) was weakened. This indicated that the absence of METTL5 primarily reduces the "ability to build bone." Next, we examined the cells that give rise to osteoblasts and found that in cells lacking METTL5, the transformation into osteoblasts and calcification were less likely to occur. Furthermore, METTL5 deficiency resulted in insufficient production of a protein called OSER1, reducing its ability to protect cells from oxidative stress. As a result, bone-forming cells became more susceptible to damage, hindering bone formation. Finally, when the antioxidant NAC was administered, the antioxidant function and bone-forming ability of cells affected by METTL5 deficiency were partially restored. In mice, bone loss and growth abnormalities were partially improved.

　These results reveal that METTL5 protects osteoblasts from oxidative stress and maintains normal bone formation by supporting OSER1 production. This study demonstrates a novel mechanism linking RNA modification and bone formation. (Figure: Modified from Figures 1A and 1F of the paper. METTL5-deficient mice exhibit reduced body size and decreased bone mass.)

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[Future Developments]

In the future, we will clarify how this mechanism is involved in human bone growth and bone diseases, and advance our understanding of the pathogenesis of METTL5-related diseases and osteogenesis imperfecta. Furthermore, we aim to investigate the possibility of antioxidant regulation using NACs and other substances, and use this to develop new treatments.

<Comment from co-author> Professor Shoichiro Furukabu, Division of Biochemistry

[Terminology]

*1 METTL5: One of the enzymes that chemically modifies RNA. In particular, it is known as an enzyme that modifies RNA contained in ribosomes, which are the machinery for protein synthesis, by adding m6A modification. In recent years, its association with developmental abnormalities and neurological disorders has been reported.

*2 OSER1: Abbreviation for Oxidative stress responsive serine-rich protein 1. A protein involved in how cells respond to oxidative stress.

*3 Osteoblasts: Cells that create bone. They produce the components that form the foundation of bone and promote bone formation by depositing calcium and other substances onto them.

*4 N-acetylcysteine ​​(NAC): One of the antioxidants. It is involved in the synthesis of glutathione, an antioxidant molecule that works within cells.

*5 Mesenchymal stem cells: Cells that have the ability to differentiate into cells such as bone, cartilage, and fat. They are one of the cells that give rise to osteoblasts.

*6 Ribosomal RNA: RNA that makes up ribosomes, which are the machinery that produces proteins in cells.

*7 m6A modification: One of the representative chemical modifications added to RNA. It is involved in the process of protein synthesis from RNA and the regulation of gene function.

[Paper title]

Title: METTL5 deficiency impairs osteogenesis through OSER1-dependent antioxidant regulation
Author: Kexin Lei, Qi Yin, Qiwen Li, Qian Wang, Zhong Zhang, Fei Xue, Ruoshi Xu, Xinyi Zhou, Lin Peng, Shoichiro Kokabu, Shuibin Lin, Quan Yuan
Journal: JCI Insight
DOI: 10.1172/jci.insight.194068

[Acknowledgment]

This research was supported by the Ministry of Education, Culture, Sports, Science and Technology and the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research, International Collaborative Research Acceleration Fund (Enhancement of International Collaborative Research (B)), 22KK0141.

[Contact]

Kyushu Dental University, Division of Biochemistry
Professor Shoichiro Kokabu
E-mail: r14kokabu■fa.kyu-dent.ac.jp
*When sending, please replace ■ with @.

[About Kyushu Dental College, a Public University Corporation]

Kyushu Dental College is the only public dental school and dental college in Japan, and is a "comprehensive university of oral medicine" consisting of a department of dentistry and a department of oral health care. We believe that dentistry is medical care that supports daily life and happiness through "oral health." In the Faculty of Dentistry and the Graduate School of Dentistry, we are committed to nurturing dental professionals. In addition, since its opening in 1914, the attached hospital has continued to serve as a core hospital with dental expertise that is closely connected to the local community.

Outline

• Press release document (PDF: 797KB)