The "orphan recipient" is not alone

■ Trainee reporter Diao Wenhui

For a long time, people think that bone is only an organ with a supporting and protective effect, and in the past 20 years, it has gradually been found that bone can also be used as a secretory organ, through the secretion of different bone-derived factors, it has an impact on various organs other than bone, and has regulatory functions on the central nervous system, immune system, energy metabolism and other aspects.

Previous studies have found that osteocalcin can act on neurons through the blood-brain barrier, regulate the central nervous system, and have an impact on the cognitive memory function of the brain. However, the specific mechanisms by which osteogenic factors regulate extraosseous organ function, particularly the central nervous system, are not well understood.

Recently, the relevant research results of Li Xiang's team at the Institute of Brain Cognition and Brain Diseases of the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences were published in Scientific Progress. Over a period of four years, the team discovered the key regulatory role of osteocalcin on oligodendrocytes in the central nervous system, and for the first time defined a new receptor that mediates the new central function of osteocalcin, the G protein-coupled receptor (GPR37).

Starting from bone-derived factors, explore the mysteries of nerves

If the axons of neurons are likened to antennas, then the myelin sheath is the insulating layer of the outer layer of the antenna, which protects the signaling of neurons. In the brain, in addition to a large number of neuronal cells, there are also many glial cells, play a role in connecting and supporting various nerve components, distributing nutrients, participating in repair and phagocytosis, oligodendrocytes are the key cells that form the myelin sheath of the central nervous system, which has a very critical role in maintaining the normal function of neurons, forming an insulating myelin structure, and assisting in the efficient transmission of bioelectrical signals.

Abnormal function of oligodendrocytes may damage the structure of the myelin sheath, cause myelin lesions and neuronal damage, and lead to nervous system dysfunction, causing a series of neurological or psychiatric disorders, such as multiple sclerosis.

In the early stage of the study, the research team used the mice that knocked out the osteocalcin gene to find that the thickness of the myelin sheath increased by immunostaining, protein hybridization, and electron microscopy analysis, and the researchers confirmed that osteocalcin has an important effect on the main component of the myelin sheath - oligodendrocytes, 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, and the myelin sheath is too thick or too thin is a manifestation of dysplasia, which can easily lead to various diseases such as movement disorders, abnormal posture, perception, communication and behavior disorders, and backward intellectual development." When the human body is upright, walking, sitting, and running, it will stimulate the bone to secrete osteocalcin to a certain extent, which in turn affects the differentiation function of oligodendrocytes in the myelin sheath and has a certain regulatory effect on the central nervous system. Li Xiang said.

Define a new signal receiver

What exactly does receiving osteocalcin signals play a role in the central nervous system? In order to further explore what receptors osteocalcin binds to and thus affect glial cells, the research team used RNA gene sequencing to compare the RNA expression of the callosum region of osteocalcin knockout mice and wild mice, and identified GPR37 as a new receptor for osteocalcin in the central nervous system for the first time.

In the human genome library, there is a class of "orphan receptors" that scientists have discovered that cannot define their role and match substances. This includes GPR37.

In the verification experiment, the research team used the osteocalcitonin knockout gene model and the GPR37 gene knockout animal model to verify the role of osteocalcin in regulating the differentiation and myelination of the central nervous system oligodendrocytes through GPR37 by integrating multidisciplinary research methods such as electron microscopy analysis, immunostaining, and behavioral analysis, which provided an experimental basis for the treatment of central myelin lesions with osteocalcin as a potential peripheral target.

"Through cooperation with the Institute of Biophysics of the Chinese Academy of Sciences, ZEISS China, and BGI, we have mutually verified the important results of this study under different technical means." Li Xiang said.

By in-depth exploration of the internal regulation mechanism of osteocalcin in the central nervous system, the research team 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.

Source: China Science Daily