A missense mutation sheds light on a novel structure-function relationship of RANKL.
Animals
Bone Resorption
Hydrophobic and Hydrophilic Interactions
Mice
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Mutation, Missense
Osteoclasts
/ metabolism
Osteogenesis
Protein Conformation
Protein Folding
Protein Stability
RANK Ligand
/ chemistry
RAW 264.7 Cells
Rats
Signal Transduction
Structure-Activity Relationship
RANKL trimerization
osteoclasts
protein structures
rRANKL M200s
signal transduction
Journal
Journal of cellular physiology
ISSN: 1097-4652
Titre abrégé: J Cell Physiol
Pays: United States
ID NLM: 0050222
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
01
05
2020
revised:
26
08
2020
accepted:
28
08
2020
pubmed:
24
9
2020
medline:
21
9
2021
entrez:
23
9
2020
Statut:
ppublish
Résumé
The tumor necrosis factor (TNF)-like core domain of receptor activator of nuclear factor-κB ligand (RANKL) is a functional domain critical for osteoclast differentiation. One of the missense mutations identified in patients with osteoclast-poor autosomal recessive osteopetrosis (ARO) is located in residue methionine 199 that is replaced with lysine (M199K) amid the TNF-like core domain. However, the structure-function relationship of this mutation is not clear. Sequence-based alignment revealed that the fragment containing human M199 is highly conserved and equivalent to M200 in rat. Using site-directed mutagenesis, we generated three recombinant RANKL mutants M200K/A/E (M200s) by replacing the methionine 200 with lysine (M200K), alanine (M200A), and glutamic acid (M200E), representative of distinct physical properties. TRAcP staining and bone pit assay showed that M200s failed to support osteoclast formation and bone resorption, accompanied by impaired osteoclast-related signal transduction. However, no antagonistic effect was found in M200s against wild-type rat RANKL. Analysis of the crystal structure of RANKL predicted that this methionine residue is located within the hydrophobic core of the protein, thus, likely to be crucial for protein folding and stability. Consistently, differential scanning fluorimetry analysis suggested that M200s were less stable. Western blot analysis analyses further revealed impaired RANKL trimerization by M200s. Furthermore, receptor-ligand binding assay displayed interrupted interaction of M200s to its intrinsic receptors. Collectively, our studies revealed the molecular basis of human M199-induced ARO and elucidated the indispensable role of rodent residue M200 (equivalent to human M199) for the RANKL function.
Substances chimiques
RANK Ligand
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2800-2816Informations de copyright
© 2020 Wiley Periodicals LLC.
Références
Anderson, D. M., Maraskovsky, E., Billingsley, W. L., Dougall, W. C., Tometsko, M. E., Roux, E. R., …Galibert, L. (1997). A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature, 390(6656), 175-179. https://doi.org/10.1038/36593
Ang, E. S., Zhang, P., Steer, J. H., Tan, J. W., Yip, K., Zheng, M. H., … Xu, J. (2007). Calcium/calmodulin-dependent kinase activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kappa B ligand (RANKL). Journal of Cellular Physiology, 212, 787-795.
Aoki, K., Saito, H., Itzstein, C., Ishiguro, M., Shibata, T., Blanque, R., … Baron, R. (2006). A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss. Journal of Clinical Investigation, 116, 1525-1534.
Asagiri, M., Sato, K., Usami, T., Ochi, S., Nishina, H., Yoshida, H., … Takayanagi, H. (2005). Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. Journal of Experimetnal Medicine, 202(9), 1261-1269. https://doi.org/10.1084/jem.20051150
Blazquez-Medela, A. M., Garcia-Ortiz, L., Gomez-Marcos, M. A., Recio-Rodriguez, J. I., Sanchez-Rodriguez, A., Lopez-Novoa, J. M., & Martinez-Salgado, C. (2012). Osteoprotegerin is associated with cardiovascular risk in hypertension and/or diabetes. European Journal of Clinical Investigation, 42(5), 548-556. https://doi.org/10.1111/j.1365-2362.2011.02619.x
Blazquez-Medela, A. M., Lopez-Novoa, J. M., & Martinez-Salgado, C. (2011). Osteoprotegerin and diabetes-associated pathologies. Current Molecular Medicine, 11(5), 401-416.
Body, J. J., Greipp, P., Coleman, R. E., Facon, T., Geurs, F., Fermand, J. P., … Bekker, P. J. (2003). A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer, 97(3 Suppl), 887-892. https://doi.org/10.1002/cncr.11138
Boonen, S., Adachi, J. D., Man, Z., Cummings, S. R., Lippuner, K., Torring, O., … McClung, M. (2011). Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. Journal of Clinical Endocrinology and Metabolism, 96(6), 1727-1736. https://doi.org/10.1210/jc.2010-2784
Boyle, W. J., Simonet, W. S., & Lacey, D. L. (2003). Osteoclast differentiation and activation. Nature, 423(6937), 337-342. https://doi.org/10.1038/nature01658
Cheng, T., Pavlos, N. J., Wang, C., Tan, J. W., Lin, J. M., Cornish, J., … Xu, J. (2009). Mutations within the TNF-like core domain of RANKL impair osteoclast differentiation and activation. Molecular Endocrinology, 23(1), 35-46. https://doi.org/10.1210/me.2007-0465
Chung, J. Y., Park, Y. C., Ye, H., & Wu, H. (2002). All TRAFs are not created equal: Common and distinct molecular mechanisms of TRAF-mediated signal transduction. Journal of Cell Science, 115(Pt 4), 679-688.
Cummings, S. R., San Martin, J., McClung, M. R., Siris, E. S., Eastell, R., Reid, I. R., … Trial, F. (2009). Denosumab for prevention of fractures in postmenopausal women with osteoporosis. New England Journal of Medicine, 361(8), 756-765. https://doi.org/10.1056/NEJMoa0809493
Douni, E., Rinotas, V., Makrinou, E., Zwerina, J., Penninger, J. M., Eliopoulos, E., … Kollias, G. (2012). A RANKL G278R mutation causing osteopetrosis identifies a functional amino acid essential for trimer assembly in RANKL and TNF. Human Molecular Genetics, 21(4), 784-798. https://doi.org/10.1093/hmg/ddr510
Eastell, R., Christiansen, C., Grauer, A., Kutilek, S., Libanati, C., McClung, M. R., … Cummings, S. R. (2011). Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. Journal of Bone and Mineral Research, 26(3), 530-537. https://doi.org/10.1002/jbmr.251
Feeley, B. T., Liu, N. Q., Conduah, A. H., Krenek, L., Roth, K., Dougall, W. C., … Lieberman, J. R. (2006). Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration. Journal of Bone and Mineral Research, 21(10), 1571-1580. https://doi.org/10.1359/jbmr.060706
Feng, X. (2005). Regulatory roles and molecular signaling of TNF family members in osteoclasts. Gene, 350(1), 1-13. https://doi.org/10.1016/j.gene.2005.01.014
Galibert, L., Tometsko, M. E., Anderson, D. M., Cosman, D., & Dougall, W. C. (1998). The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. Journal of Biological Chemistry, 273(51), 34120-34127.
Garrett, I. R., Boyce, B. F., Oreffo, R. O., Bonewald, L., Poser, J., & Mundy, G. R. (1990). Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. Journal of Clinical Investigation, 85(3), 632-639. https://doi.org/10.1172/JCI114485
Golden, D., Saria, E. A., & Hansen, M. F. (2015). Regulation of osteoblast migration involving receptor activator of nuclear factor-kappa B (RANK) signaling. Journal of Cellular Physiology, 230(12), 2951-2960. https://doi.org/10.1002/jcp.25024
Guerrini, M. M., Sobacchi, C., Cassani, B., Abinun, M., Kilic, S. S., Pangrazio, A., … Frattini, A. (2008). Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. American Journal of Human Genetics, 83(1), 64-76. https://doi.org/10.1016/j.ajhg.2008.06.015
Hanada, R., Leibbrandt, A., Hanada, T., Kitaoka, S., Furuyashiki, T., Fujihara, H., … Penninger, J. M. (2009). Central control of fever and female body temperature by RANKL/RANK. Nature, 462(7272), 505-509. https://doi.org/10.1038/nature08596
Hikita, A., & Tanaka, S. (2007). Ectodomain shedding of receptor activator of NF-kappaB ligand. Advances in Experimental Medicine and Biology, 602, 15-21.
Huang, L., Xu, J., Wood, D. J., & Zheng, M. H. (2000). Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kappaB in giant cell tumor of bone: Possible involvement in tumor cell-induced osteoclast-like cell formation. American Journal of Pathology, 156(3), 761-767.
Hwang, S. Y., & Putney, J. W., Jr. (2011). Calcium signaling in osteoclasts. Biochimica et Biophysica Acta, 1813(5), 979-983. https://doi.org/10.1016/j.bbamcr.2010.11.002
Ikebuchi, Y., Aoki, S., Honma, M., Hayashi, M., Sugamori, Y., Khan, M., … Suzuki, H. (2018). Coupling of bone resorption and formation by RANKL reverse signalling. Nature, 561(7722), 195-200. https://doi.org/10.1038/s41586-018-0482-7
Jones, D. H., Nakashima, T., Sanchez, O. H., Kozieradzki, I., Komarova, S. V., Sarosi, I., … Penninger, J. M. (2006). Regulation of cancer cell migration and bone metastasis by RANKL. Nature, 440(7084), 692-696. https://doi.org/10.1038/nature04524
Kajiya, H. (2012). Calcium signaling in osteoclast differentiation and bone resorption. Advances in Experimental Medicine and Biology, 740, 917-932. https://doi.org/10.1007/978-94-007-2888-2_41
Kiesel, L., & Kohl, A. (2016). Role of the RANK/RANKL pathway in breast cancer. Maturitas, 86, 10-16. https://doi.org/10.1016/j.maturitas.2016.01.001
Kim, H. S., Nam, S. T., Mun, S. H., Lee, S. K., Kim, H. W., Park, Y. H., … Choi, W. S. (2017). DJ-1 controls bone homeostasis through the regulation of osteoclast differentiation. Nature Communications, 8(1):1519. https://doi.org/10.1038/s41467-017-01527-y
Laird, R. K., Pavlos, N. J., Xu, J., Brankov, B., White, B., Fan, Y., … Zheng, M. H. (2006). Bone allograft non-union is related to excessive osteoclastic bone resorption: A sheep model study. Histology and Histopathology, 21(12), 1277-1285. https://doi.org/10.14670/HH-21.1277
Lam, J., Nelson, C. A., Ross, F. P., Teitelbaum, S. L., & Fremont, D. H. (2001). Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity. Journal of Clinical Investigation, 108(7), 971-979. https://doi.org/10.1172/JCI13890
Lee, N. K., Choi, Y. G., Baik, J. Y., Han, S. Y., Jeong, D. W., Bae, Y. S., … Lee, S. Y. (2005). A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood, 106(3), 852-859. https://doi.org/10.1182/blood-2004-09-3662
Liu, C., Walter, T. S., Huang, P., Zhang, S., Zhu, X., Wu, Y., … Gao, B. (2010). Structural and functional insights of RANKL-RANK interaction and signaling. Journal of Immunology, 184(12), 6910-6919. https://doi.org/10.4049/jimmunol.0904033
Liu, D., Xu, J. K., Figliomeni, L., Huang, L., Pavlos, N. J., Rogers, M., … Zheng, M. H. (2003). Expression of RANKL and OPG mRNA in periodontal disease: Possible involvement in bone destruction. International Journal of Molecular Medicine, 11(1), 17-21.
Liu, W., Xu, D., Yang, H., Xu, H., Shi, Z., Cao, X., … Feng, X. (2004). Functional identification of three receptor activator of NF-kappa B cytoplasmic motifs mediating osteoclast differentiation and function. Journal of Biological Chemistry, 279(52), 54759-54769. https://doi.org/10.1074/jbc.M404687200
Liu, C., Zhao, Y., He, W., Wang, W., Chen, Y., Zhang, S., … Gao, B. (2015). A RANKL mutant used as an inter-species vaccine for efficient immunotherapy of osteoporosis. Scientific Reports, 5, 14150. https://doi.org/10.1038/srep14150
Maser, R. E., Lenhard, M. J., Sneider, M. B., & Pohlig, R. T. (2015). Osteoprotegerin is a better serum biomarker of coronary artery calcification than osteocalcin in type 2 diabetes. Endocrine Practice, 21(1), 14-22. https://doi.org/10.4158/EP14229.OR
Motiur Rahman, M., Takeshita, S., Matsuoka, K., Kaneko, K., Naoe, Y., Sakaue-Sawano, A., … Ikeda, K. (2015). Proliferation-coupled osteoclast differentiation by RANKL: Cell density as a determinant of osteoclast formation. Bone, 81, 392-399. https://doi.org/10.1016/j.bone.2015.08.008
Naismith, J. H., & Sprang, S. R. (1998). Modularity in the TNF-receptor family. Trends in Biochemical Sciences, 23(2), 74-79. https://doi.org/10.1016/s0968-0004(97)01164-x
Nelson, C. A., Warren, J. T., Wang, M. W., Teitelbaum, S. L., & Fremont, D. H. (2012). RANKL employs distinct binding modes to engage RANK and the osteoprotegerin decoy receptor. Structure, 20(11), 1971-1982. https://doi.org/10.1016/j.str.2012.08.030
Nilsberth, C., Westlind-Danielsson, A., Eckman, C. B., Condron, M. M., Axelman, K., Forsell, C., … Lannfelt, L. (2001). The “Arctic” APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nature Neuroscience, 4(9), 887-893. https://doi.org/10.1038/nn0901-887
Palumbo, S., & Li, W. J. (2013). Osteoprotegerin enhances osteogenesis of human mesenchymal stem cells. Tissue Engineering. Part A, 19(19-20), 2176-2187. https://doi.org/10.1089/ten.TEA.2012.0550
Pangrazio, A., Cassani, B., Guerrini, M. M., Crockett, J. C., Marrella, V., Zammataro, L., … Sobacchi, C. (2012). RANK-dependent autosomal recessive osteopetrosis: Characterization of five new cases with novel mutations. Journal of Bone and Mineral Research, 27(2), 342-351. https://doi.org/10.1002/jbmr.559
Romas, E., Sims, N. A., Hards, D. K., Lindsay, M., Quinn, J. W., Ryan, P. F., … Gillespie, M. T. (2002). Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. American Journal of Pathology, 161(4), 1419-1427. https://doi.org/10.1016/S0002-9440(10)64417-3
Roux, S., Meignin, V., Quillard, J., Meduri, G., Guiochon-Mantel, A., Fermand, J. P., … Mariette, X. (2002). RANK (receptor activator of nuclear factor-kappaB) and RANKL expression in multiple myeloma. British Journal of Haematology, 117(1), 86-92.
Silva, I., & Branco, J. C. (2011). RANK/RANKL/OPG: Literature review. Acta Reumatológica Portuguesa, 36(3), 209-218.
Sobacchi, C., Frattini, A., Guerrini, M. M., Abinun, M., Pangrazio, A., Susani, L., … Helfrich, M. H. (2007). Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nature Genetics, 39(8), 960-962. https://doi.org/10.1038/ng2076
Sobacchi, C., Schulz, A., Coxon, F. P., Villa, A., & Helfrich, M. H. (2013). Osteopetrosis: Genetics, treatment and new insights into osteoclast function. Nature Reviews Endocrinology, 9(9), 522-536. https://doi.org/10.1038/nrendo.2013.137
Song, D., Cao, Z., Liu, Z., Tickner, J., Qiu, H., Wang, C., … Xu, J. (2018). Cistanche deserticola polysaccharide attenuates osteoclastogenesis and bone resorption via inhibiting RANKL signaling and reactive oxygen species production. Journal of Cellular Physiology, 233(12), 9674-9684. https://doi.org/10.1002/jcp.26882
Soto, C. (2003). Unfolding the role of protein misfolding in neurodegenerative diseases. Nature Reviews Neuroscience, 4(1), 49-60. https://doi.org/10.1038/nrn1007
Studer, R. A., Dessailly, B. H., & Orengo, C. A. (2013). Residue mutations and their impact on protein structure and function: Detecting beneficial and pathogenic changes. Biochemical Journal, 449(3), 581-594. https://doi.org/10.1042/BJ20121221
Ta, H. M., Nguyen, G. T., Jin, H. M., Choi, J., Park, H., Kim, N., … Kim, K. K. (2010). Structure-based development of a receptor activator of nuclear factor-kappaB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis. Proceedings of the National Academy of Sciences of the United States of America, 107(47), 20281-20286. https://doi.org/10.1073/pnas.1011686107
Takayanagi, H., Kim, S., Koga, T., Nishina, H., Isshiki, M., Yoshida, H., … Taniguchi, T. (2002). Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Developmental Cell, 3(6), 889-901.
Teitelbaum, S. L. (2000). Bone resorption by osteoclasts. Science, 289(5484), 1504-1508.
Venuraju, S. M., Yerramasu, A., Corder, R., & Lahiri, A. (2010). Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. Journal of the American College of Cardiology, 55(19), 2049-2061. https://doi.org/10.1016/j.jacc.2010.03.013
Wang, C., Steer, J. H., Joyce, D. A., Yip, K. H., Zheng, M. H., & Xu, J. (2003). 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits osteoclastogenesis by suppressing RANKL-induced NF-kappaB activation. Journal of Bone and Mineral Research, 18(12), 2159-2168. https://doi.org/10.1359/jbmr.2003.18.12.2159
Xu, J., Tan, J. W., Huang, L., Gao, X. H., Laird, R., Liu, D., … Zheng, M. H. (2000). Cloning, sequencing, and functional characterization of the rat homologue of receptor activator of NF-kappaB ligand. Journal of Bone and Mineral Research, 15(11), 2178-2186. https://doi.org/10.1359/jbmr.2000.15.11.2178
Xu, J., Wu, H. F., Ang, E. S., Yip, K., Woloszyn, M., Zheng, M. H., & Tan, R. X. (2009). NF-kappaB modulators in osteolytic bone diseases. Cytokine and Growth Factor Reviews, 20(1), 7-17. https://doi.org/10.1016/j.cytogfr.2008.11.007
Yamashita, T., Yao, Z., Li, F., Zhang, Q., Badell, I. R., Schwarz, E. M., … Boyce, B. F. (2007). NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. Journal of Biological Chemistry, 282(25), 18245-18253. https://doi.org/10.1074/jbc.M610701200
Yip, K. H., Feng, H., Pavlos, N. J., Zheng, M. H., & Xu, J. (2006). p62 ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-kappaB ligand-induced osteoclast formation: A new insight into the pathogenesis of Paget's disease of bone. American Journal of Pathology, 169(2), 503-514.
Yip, K. H., Zheng, M. H., Steer, J. H., Giardina, T. M., Han, R., Lo, S. Z., … Xu, J. (2005). Thapsigargin modulates osteoclastogenesis through the regulation of RANKL-induced signaling pathways and reactive oxygen species production. Journal of Bone and Mineral Research, 20(8), 1462-1471. https://doi.org/10.1359/JBMR.050324
Zhang, S., Wang, X., Li, G., Chong, Y., Zhang, J., Guo, X., … Bi, Z. (2017). Osteoclast regulation of osteoblasts via RANKRANKL reverse signal transduction in vitro. Molecular Medicine Reports, 16(4), 3994-4000. https://doi.org/10.3892/mmr.2017.7039
Zhu, Y. J., Lin, H., & Lal, R. (2000). Fresh and nonfibrillar amyloid beta protein(1-40) induces rapid cellular degeneration in aged human fibroblasts: Evidence for AbetaP-channel-mediated cellular toxicity. FASEB Journal, 14(9), 1244-1254.