RANKL/ODF Extracellular Domain (human, recombinant)

Receptor activator of NF-κB ligand (RANKL), also known as osteoclast differentiation factor (ODF), is a type II transmembrane protein and member of the TNF cytokine family that has roles in bone remodeling, osteoclast differentiation, and immune cell regulation.^1,2,3 It is composed of a cytoplasmic domain, a transmembrane domain, and an extracellular binding domain.^1,2,3 RANKL is widely expressed but is highly expressed in precursor osteoclasts and maturing lymphocytes.^4,5,6 It binds as a soluble homotrimer to its receptor, RANK, to induce signaling via the NF-κB, JNK, ERK, p38, nuclear factor of activated T cells (NFAT), and Akt pathways.^7,8,1 RANKL also binds to osteoprotegrin (OPG), which prevents RANKL from activating RANK signaling.⁹ TNFSF11, the gene encoding RANKL, is differentially transcribed to produce three isoforms: RANKL 1 and RANKL 2, which contain all three domains, and RANKL 3, which contains only the extracellular domain.³ The extracellular domain can also be cleaved from full-length RANKL by the proteases disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) or matrix metalloproteinases-7 (MMP-7) to produce soluble RANKL extracellular domain.⁶ RANKL 1 promotes osteoclastogenesis while RANKL 3 decreases the ratio of osteoclasts to preosteoclasts. Recombinant RANKL extracellular domain induces dendritic cell aggregation and clustering and increases dendritic cell activation.² Serum levels of the RANKL extracellular domain are elevated in patients with multiple myeloma and are negatively correlated with prognosis.⁵ Cayman’s RANKL/ODF Extracellular Domain (human, recombinant) protein can be used for binding and cellular activity assay applications. This protein is a disulfide-linked homodimer. The reduced monomer, composed of RANKL/ODF Extracellular Domain (amino acids 64-245) fused to rabbit IgG Fc at its N-terminus, consists of 181 amino acids and has a calculated molecular weight of 134.21 kDa. As a result of glycosylation, the monomer migrates at approximately 45-55 kDa by SDS-PAGE under reducing conditions.

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1. Liu, C., Zhao, Y., He, W., et al. A RANKL mutant used as an inter-species vaccine for efficient immunotherapy of osteoporosis. Sci. Rep. 5, 14150 (2015).

2. Anderson, D.M., Maraskovsky, E., Billingsley, W.L., et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390(6656), 175-179 (1997).

3. Suzuki, J., Ikeda, T., Kuroyama, H., et al. Regulation of osteoclastogenesis by three human RANKL isoforms expressed in NIH3T3 cells. Biochem. Biophys. Res. Commun. 314(4), 1021-1027 (2004).

4. Pan, A., Chen, M., Chowdhury, R., et al. α-Linolenic acid and risk of cardiovascular disease: A systematic review and meta-analysis. Am. J. Clin. Nutr. 96(6), 1262-1273 (2012).

5. Terpos, E., Szydlo, R., Apperley, J.F., et al. Soluble receptor activator of nuclear factor κB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: Proposal for a novel prognostic index. Blood 102(3), 1064-1069 (2003).

6. Renema, N., Navet, B., Heymann, M.-F., et al. RANK-RANKL signalling in cancer. Biosci. Rep. 36(4), e00366 (2016).

7. Amirhosseini, M., Bernhardsson, M., Lång, P., et al. Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing. J. Cell. Physiol. 234(9), 16503-16516 (2019).

8. He, Y.-Q., Zhang, Q., Shen, Y., et al. Rubiadin-1-methyl ether from Morinda officinalis How. Inhibits osteoclastogenesis through blocking RANKL-induced NF-κB pathway. Biochem. Biophys. Res. Commun. 506(4), 927-931 (2018).

9. Willard, D., Chen, W.-J., Barrett, G., et al. Expression, purification, and characterization of the human receptor activator of NF-κB ligand (RANKL) extracellular domain. Protein Expr. Purif. 20(1), 48-57 (2000).