Osteocalcin (OCN) is a multifunctional bone-derived hormone that modulates numerous physiological activities. OCN can cross the blood brain barrier (BBB) and thus play critical roles in neuronal and brain development. 

Fully elucidating the exact function of OCN in central nervous system (CNS) is significant for the discovery of therapeutic target in treating CNS disorders. 

A research team led by LI Xiang from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences revealed the molecular mechanism of oligodendrocyte myelination by OCN in the CNS. 

Their study was published in Science Advances on Oct. 22. 

A schematic mechanism depicting the action of OCN on myelin regulation in oligodendrocyte. (Image by SIAT) 

The researchers first investigated the effects of OCN on CNS myelination using OCN deficient mouse. By combination of immunostaining, western blotting and electron microscopy analysis, they found that OCN deletion results in hypermyelination in the CNS. 

Oligodendrocytes (OLs) are glial cells that form myelin in the CNS. To clarify the mechanism of OCN in CNS myelination, the researchers further investigated whether OCN play a role in regulation of OL differentiation and myelination. 

By using OCN deficient mouse, primary OL culture and exogenous OCN treatment, they found that genetic deletion of OCN facilitated OL differentiation and hypermyelination through the transcription factor Myrf in the CNS. Although dispensable for the proliferation of oligodendrocyte precursor cells (OPCs), OCN was critical for the myelination of OLs, which affected myelin production and remyelination after demyelinating injury. 

To identify the receptor for OCN in OL, they combined RNA sequence, heterologous systems biophysics analysis, in vivo mouse model validation, and finally prove that GPR37 is the receptor for OCN and mediates its function in OL. 

These findings not only expand a new role of the OCN hormone in the CNS, but also demonstrate a molecular basis for OCN function by activation of the GPR37 signaling. This study provides a unique perspective for the understanding of mutual communication between the skeleton biology and glial functions.