Dr. Tadayoshi Hayata

Department of Molecular Pharmacology, Faculty of Pharmaceutical Science, Tokyo University of Science

Osteoporosis is a highly prevalent disease affecting at least nearly 200 million people worldwide and is life-threatening in elderly patients. Bone-resorbing cells called osteoclasts are derived from a type of immune cells called macrophages. They are necessary for the maintenance and renewal of bones. But the post-transcriptional mechanisms through which macrophages differentiate into osteoclasts are not fully understood. In this study, we focused on two genes CNOT3 and Cpeb4 that are involved in post-transcriptional regulation. Cnot3 is a subunit of CCR4-NOT complex that mediates deadenylation of mRNAs. Cpeb4 is an RNA-binding protein that is known to cooperate with CCR4-NOT complex. We discovered that Cnot3 deficiency specifically enhances receptor activator of NF-κB (RANK) mRNA stability and leads to osteopenia in healthy young adult animals ⁽¹⁾. Moreover, Cnot3 levels are reduced in ageing-induced osteoporosis, and Cnot3 deficiency further exacerbates such osteoporosis significantly. As a mechanism, Cnot3 binds to RANK mRNA and its 3′-UTR renders Cnot3-dependent instability to the reporter gene. We also discovered that Cpeb4 is required for RANKL-induced osteoclast differentiation in mouse macrophage-derived RAW264.7 cell line ⁽²⁾. These results suggest that Cnot3 and Cpeb4 are negative and positive regulators in osteoclastogenesis, respectively. Our findings suggest potential therapeutic targets for osteoporosis.

1. Watanabe C, Morita M, Hayata T, Nakamoto T, Kikuguchi C, Xue Li, Kobayashi Y, Takahashi N, Notomi T, Moriyama K, Yamamoto T, Ezura Y*, Noda M*. The stability of mRNA influences osteoporotic bone mass via CNOT3. Proc Natl Acad Sci U S A. 2014;111:2692-7.
2. Arasaki Y, Li M, Akiya T, Nozawa I, Ezura Y, Hayata T. The RNA-binding protein Cpeb4 is a novel positive regulator of osteoclast differentiation. Biochem Biophys Res Commun. 2020;528(4):621-627.

Tadayoshi Hayata Ph.D. is an associate professor in Department of Molecular Pharmacology, Faculty of Pharmaceutical Science, Tokyo University of Science since 2018. He graduated from Department of Biology, Faculty of Science, The University of Tokyo in 1996. He studied developmental biology and obtained his Ph.D. under the supervision of Professor Makoto Asashima in Graduate School of Arts and Sciences, The University of Tokyo in 2001. He continued developmental biology research as a postgraduate researcher in Professor Ken Cho lab in University of California, Irvine from 2001 to 2005. He studied bone biology as an assistant professor under the supervision of Professor Masaki Noda in Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical & Dental University from 2005 to 2014. In 2014, he became an associate professor in Faculty of Medicine, University of Tsukuba. And then he was appointed to current position in 2018. His research interests lie in the area of bone biology especially focused on cellular signalling.