Researchers provide new understanding on bone diseases

TOKYO: Diseases of the bones and joints are becoming more common among today's elderly. For example, roughly 12 million people in Japan suffer from osteoporosis, a condition that causes substantial bone weakness and fragility.

Understanding the basic processes that maintain bone and joint tissue is a critical first step toward developing effective treatments for these diseases. Osteoclasts are a type of cell that plays a crucial role in bone maintenance. These cells absorb and break down old or broken bones, letting the body reuse key elements such as calcium and creating space for new bones.

As one may assume, many bone diseases develop when osteoclasts do not perform their functions adequately. Scientists are exploring the processes that control the proliferation and differentiation of precursor cells into osteoclasts. Interestingly, in a study published in 2020, researchers from Tokyo University of Science (TUS) led by Professor Tadayoshi Hayata revealed that the cytoplasmic polyadenylation element-binding protein 4 (Cpeb4) protein is essential in osteoclast differentiation. They also discovered that this protein, which regulates the stability and translation of messenger RNA (mRNA) molecules, was transported into specific structures within the nucleus of the cell when osteoclast differentiation was induced.

However, just how this relocation occurs and what Cpeb4 exactly does within these nuclear structures remains a mystery. Now, in a recent study published in the Journal of Cellular Physiology, Prof. Hayata and Yasuhiro Arasaki from TUS tackled these knowledge gaps. Motivated by the intricate and complex process of osteoclast differentiation, they sought to more thoroughly understand how the "life cycle" of mRNA, i.e., mRNA metabolism, is involved.

First, the researchers introduced strategic modifications to Cpeb4 proteins and performed a series of experiments in cell cultures. They found that the localization of Cpbe4 in the abovementioned nuclear bodies occurred owing to its ability to bind to RNA molecules. Afterwards, seeking to understand the role of Cpeb4 in the nucleus, the researchers demonstrated that Cpeb4 co-localized with certain mRNA splicing factors. These proteins are involved in the process of mRNA splicing, which is a key step in mRNA metabolism. Put simply, it enables a cell to produce diverse mature mRNA molecules (and eventually proteins) from a single gene.

Through RNA sequencing and gene analysis in Cpeb4-depleted cells, they found that Cpeb4 alters the expression of multiple genes associated with splicing events in freshly differentiated osteoclasts. Finally, through further experiments, the researchers revealed that Cpeb4 only altered the splicing patterns of Id2 mRNA, an important protein known to regulate osteoclast differentiation and development.