OPG

OPG (osteoprotegerin)， As a bone protective factor, it is translated into Chinese as osteoprotegerin. It was discovered by two research groups in the United States and Japan in 1997.

OPG belongs to the TNF receptor (TNFR) superfamily, also known as the TNF bait receptor (soluble receptor). OPG protein contains 380 amino acids and is a secreted glycoprotein lacking a transmembrane domain. It serves as a soluble bait receptor and is exported to the extracellular space. The human OPG gene (gene symbol: TNFRSF11B) is located on chromosome 8 (8q24.12) and encodes a 401 amino acid receptor. The structural domain of OPG contains four pseudo repeat sequences rich in cysteine at the amino terminus and two death domains at the carboxyl terminus [2, 3].

OPG mRNA has a wide tissue distribution, with high expression levels in the liver, heart, lungs, kidneys, stomach, small intestine, skin, brain, spinal cord, and bones. Human and mouse OPG have 85% identity in their amino acid sequences. The main function of OPG is to inhibit the formation and activity of osteoclasts, but its effect is not limited to bones. Recently, it has been discovered that OPG may be an important factor in maintaining the survival of endothelial cells. OPG treatment can prevent osteoporosis and vascular calcification, as well as reverse osteoporosis.

RANKL

ReceptorActivation of Nuclear Factor - κ B Ligand (RANKL), also known as TNF related activation induced cytokine (TRANCE); Osteoprotegerin ligand (OPGL) and osteoclast differentiation factor (ODF).

RANKL is a ligand for OPG. After the discovery of OPG, the two research groups obtained OPG ligands, namely osteoprotegerin ligand (OPGL), through recombinant fusion technology screening; Subsequently, the same tumor necrosis factor (TNF) - related activation inducing cytokine (TRANCE) as the OPGL sequence was discovered, namely RANKL (nuclear factor kappa B receptor activator ligand). The American Society for Bone Mineral Research (ASBMR) standardized OPGL, TRANCE, ODF, and RANKL and named them RANKL.

The mRNA of human RANKL is mainly located in bones, bone marrow, and lymphoid tissues. Its main function is to stimulate the differentiation and activity of osteoclasts, and inhibit their apoptosis. During the differentiation of osteoclast precursors into mature osteoclasts, the presence of low-level macrophage colony-stimulating factor (M-CSF) and RANKL is necessary. RANK is expressed by osteoclast precursors and mature osteoclasts, and is the only receptor for RANKL. RANK knockout mice exhibit severe bone sclerosis due to a lack of osteoclasts.

Due to the similarity in sequence between OPGL and RANKL, OPG can selectively bind to RANKL. The only bone targeted drug currently on the market, Denosumab, is a new humanized monoclonal antibody developed by Anjin Company using genetically modified mice and modified IgG2 antibodies. It is the first RANKL inhibitor. Mainly used for the treatment of giant cell tumors of bone that cannot be surgically removed or may cause serious functional impairment after surgical removal, as well as for the prevention of bone related events in patients with multiple myeloma and solid tumor bone metastasis, and for the treatment of bisphosphonate refractory malignant tumor hypercalcemia.

With the gradual deepening of the understanding of the OPG/RANKL/RANK system, OPG and RANKL proteins are increasingly used in the treatment research of diseases characterized by excessive bone resorption, such as multiple myeloma, tumor bone metastasis, and postmenopausal osteoporosis.

References:

1. Ono, T., Hayashi, M., Sasaki, F. et al. RANKL biology: bone metabolism, the immune system, andbeyond. Inflamm Regener 40, 2 (2020).https://doi.org/10.1186/s41232-019-0111-3

2.Nakashima T, Hayashi M, Takayanagi H. New insights intoosteoclastogenic signaling mechanisms. Trends Endocrinol Metab. 2012;23:582–90.https://doi.org/10.1016/j.tem.2012.05.005.

3.Okamoto K, et al. Osteoimmunology: the conceptual frameworkunifying the immune and skeletal systems. Physiol Rev. 2017;97:1295–349.

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OPG‍

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