For a long time, people believe that bone is only an organ with support and protection. In recent 20 years, studies have gradually found that bone can also act as a secretory organ, affect various organs other than bone by secreting different bone derived factors, and regulate the central nervous system, immune system, energy metabolism and so on.

On October 22, the latest research results of Li Xiang's team from the Institute of brain cognition and brain diseases, Shenzhen Institute of advanced technology, Chinese Academy of Sciences were published in science advances. After four years, the research team discovered the key regulatory effect of osteocalcin (OCN) on oligodendrocytes in the central nervous system, and defined the G protein coupled receptor (gpr37), a brand-new receptor mediating osteocalcin, a new central function, for the first time.

Exploring the mystery of nerve from bone derived factors

If the axon of a neuron is compared to an antenna, the myelin sheath is the insulating layer of the outer layer of the antenna, which plays a protective role in the signal transduction of neurons. In the brain, in addition to hundreds of billions of neurons, there are also many glial cells, which connect and support various nerve components, distribute nutrients, participate in repair and phagocytosis, and oligodendrocytes are the key cells to form myelin sheath of the central nervous system.

As the key cells to form myelin in the central nervous system, oligodendrocytes play a very key role in maintaining the normal function of neurons, forming an insulating myelin structure and assisting in the jumping and efficient transmission of bioelectric signals. The abnormal function of oligodendrocytes may damage the myelin structure, cause myelin lesions and neuronal damage, lead to nervous system dysfunction, and lead to a series of nervous system or mental diseases, such as multiple sclerosis.

At the beginning of the study, the research team used mice with osteocalcin gene knockout to find that the thickness of myelin sheath increased after osteocalcin gene knockout by means of immunostaining, protein hybridization and electron microscope analysis. Therefore, the researchers confirmed that osteocalcin had an important impact on oligodendrocytes, the main component of myelin sheath, and further found that, The absence of osteocalcin will affect the differentiation of oligodendrocytes and the function of myelination.

"The myelin sheath gradually matures with the development of the human body. Too thick or too thin myelin sheath is a manifestation of dysplasia, which is easy to lead to various diseases such as movement disorders, abnormal posture, perception, communication and behavior disorders, mental retardation and so on. When the human body is performing human actions such as upright, walking, sitting down and running, it will stimulate the bone to secrete osteocalcin to a certain extent, and then It affects the differentiation function of oligodendrocytes in myelin sheath and has a certain regulatory effect on the central nervous system, "said Li Xiang.

"Orphan receptor" does not define a new signal receiver alone

What exactly receives osteocalcin signals and plays a role in the central nervous system? In order to further explore which receptor osteocalcin binds to and then affects glial cells, the research team used RNA gene sequencing to compare the RNA expression in the corpus callosum of osteocalcin gene knockout mice and wild mice, and determined gpr37 as a new receptor of osteocalcin in the central nervous system for the first time.

In the long history of human science, many scientists have made unremitting efforts to condense the human genome library. Among them, there is a kind of "orphan receptor", which is discovered by scientists, but can not define its role and matching substances. Among them, G protein coupled receptor (gpr37) is included.

In the validation experiment, the research team used osteocalcin knockout gene model and gpr37 gene knockout animal model to verify that osteocalcin can regulate the differentiation and myelination of oligodendrocytes in the central nervous system through gpr37 by integrating multi-disciplinary research methods such as electron microscope analysis, immunostaining and behavior analysis, This provides an experimental basis for the treatment of central myelin diseases with osteocalcin as a peripheral potential target.

"We used various gene knockout animal models and adopted different research methods, including key electron microscopic analysis, immunostaining, RNA sequencing, etc. through cooperation with the Institute of biophysics of China, Zeiss China and BGI, we mutually verified the important results of this study under different technical means," said Li Xiang.

Scientists have been exploring the effects of osteocalcin on the central nervous system. Some studies have found that osteocalcin can act on neurons through the blood-brain barrier, regulate the central nervous system and affect the brain's cognitive and memory function. However, the specific mechanism of osteogenic factors regulating the function of extraosseous organs, especially the central nervous system, is not very clear.

For the first time, the research team defined a new receptor for osteocalcin in the functional regulation of the central nervous system. By deeply exploring the internal regulation mechanism of osteocalcin in the central nervous system and looking for the key regulatory molecules of "peripheral central", it provides a theoretical basis for exploring new measures to maintain nervous system function from the perspective of regulating bone function and osteogenic factors, and provides a scientific basis for new strategies and new targets for clinical intervention of related nervous system diseases.