Skip to main content

Advertisement

SpringerLink
Log in

Genetic disorders associated with the RANKL/OPG/RANK pathway

  • Invited Review
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

The RANKL/OPG/RANK signalling pathway is a major regulatory system for osteoclast formation and activity. Mutations in TNFSF11, TNFRSF11B and TNFRSF11A cause defects in bone metabolism and development, thereby leading to skeletal disorders with changes in bone density and/or morphology. To date, nine kinds of monogenic skeletal diseases have been found to be causally associated with TNFSF11, TNFRSF11B and TNFRSF11A mutations. These diseases can be divided into two types according to the mutation effects and the resultant pathogenesis. One is caused by the mutations inducing constitutional RANK activation or OPG deficiency, which increase osteoclastogenesis and accelerate bone turnover, resulting in juvenile Paget’s disease 2, Paget disease of bone 2, familial expansile osteolysis, expansile skeletal hyperphosphatasia, panostotic expansile bone disease, and Paget disease of bone 5. The other is caused by the de-activating mutations in TNFRSF11A or TNFSF11, which decrease osteoclastogenesis and elevate bone density, resulting in osteopetrosis, autosomal recessive 2 and 7, and dysosteosclerosis. Here we reviewed the current knowledge about these genetic disorders with paying particular attention to the updating genotype–phenotype association in the TNFRSF11A-caused diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Courtesy by Dr. Pelin Özlem Simsek Kiper (Hacettepe University)

Fig. 2

Similar content being viewed by others

References

  1. Soysa NS, Neil A, Aoki K, Ohya K (2012) Osteoclast formation and differentiation: an overview. J Med Dent Sci 59:65–74

    PubMed  Google Scholar 

  2. Ikebuchi Y, Aoki S, Honma M, Hayashi M, Sugamori Y, Khan M, Kariya Y, Kato G, Tabata Y, Penninger JM, Udagawa N (2018) Coupling of bone resorption and formation by RANKL reverse signalling. Nature 561:195–200

    Article  CAS  Google Scholar 

  3. Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N, Grabowski P (2007) Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 39:960–962

    Article  CAS  Google Scholar 

  4. Lo Iacono N, Pangrazio A, Abinun M, Bredius R, Zecca M, Blair HC, Vezzoni P, Villa A, Sobacchi C (2013) RANKL cytokine: from pioneer of the osteoimmunology era to cure for a rare disease. Clin Dev Immunol 2013:412768

    Article  Google Scholar 

  5. Beard CJ, Key L, Newburger PE, Ezekowitz RA, Arceci R, Miller B, Proto P, Ryan T, Anast C, Simons ER (1986) Neutrophil defect associated with malignant infantile osteopetrosis. J Lab Clin Med 108:489–497

    Google Scholar 

  6. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH (2013) Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol 9:522–536

    Article  CAS  Google Scholar 

  7. Polyzos SA, Cundy T, Mantzoros CS (2018) Juvenile paget disease. Metabolism 80:15–26

    Article  CAS  Google Scholar 

  8. Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S (2014) Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 68:153–161

    Article  CAS  Google Scholar 

  9. Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, Mumm S (2002) Osteoprotegerin deficiency and juvenile Paget's disease. New Engl J Med 347:175–184

    Article  CAS  Google Scholar 

  10. Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, Mulley J, Love DR, Seidel J, Fawkner M, Banovic T (2002) A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11:2119–2127

    Article  CAS  Google Scholar 

  11. Chong B, Hegde M, Fawkner M, Simonet S, Cassinelli H, Coker M, Kanis J, Seidel J, Tau C, Tüysüz B, Yüksel B (2003) Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J Bone Miner Res 18:2095–2104

    Article  CAS  Google Scholar 

  12. Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, Van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24:45–48

    Article  CAS  Google Scholar 

  13. Johnson-Pais TL, Singer FR, Bone HG, McMurray CT, Hansen MF, Leach RJ (2003) Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J Bone Miner Res 18:376–380

    Article  CAS  Google Scholar 

  14. Topham DG, Sampson MJ (2016) Familial expansile osteolysis: an Australian case report of a Paget's disease mimic. J Med Imag Radiat Oncol 60:370–373

    Article  Google Scholar 

  15. Palenzuela L, Vives-Bauza C, Fernandez-Cadenas I, Meseguer A, Font N, Sarret E, Schwartz S, Andreu AL (2002) Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene. J Med Genet 39:e67

    Article  CAS  Google Scholar 

  16. Elahi E, Shafaghati Y, Asadi S, Absalan F, Goodarzi H, Gharaii N, Karimi-Nejad MH, Shahram F, Hughes AE (2007) Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation. J Bone Miner Metab 25:159–164

    Article  CAS  Google Scholar 

  17. Whyte MP, Mills BG, Reinus WR, Podgornik MN, Roodman GD, Gannon FH, Eddy MC, Mcalister WH (2000) Expansile skeletal hyperphosphatasia: a new familial metabolic bone disease. J Bone Miner Res 15:2330–2344

    Article  CAS  Google Scholar 

  18. Whyte MP, Hughes AE (2002) Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J Bone Miner Res 17:26–29

    Article  CAS  Google Scholar 

  19. Whyte MP, Mumm S (2004) Heritable disorders of the RANKL/OPG/RANK signaling pathway. J Musculoskel Neuron 4:254–267

    CAS  Google Scholar 

  20. Schafer AL, Mumm S, El-Sayed I, McAlister WH, Horvai AE, Tom AM, Hsiao EC, Schaefer FV, Collins MT, Anderson MS, Whyte MP (2014) Panostotic expansile bone disease with massive jaw tumor formation and a novel mutation in the signal peptide of RANK. J Bone Miner Res 29:911–921

    Article  CAS  Google Scholar 

  21. Nakatsuka K, Nishizawa Y, Ralston SH (2003) Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J Bone Miner Res 18:1381–1385

    Article  CAS  Google Scholar 

  22. Ke YH, Yue H, He JW, Liu YJ, Zhang ZL (2009) Early onset Paget's disease of bone caused by a novel mutation (78dup27) of the TNFRSF11A gene in a Chinese family. Acta Pharmacol Sin 30:1204–1210

    Article  CAS  Google Scholar 

  23. Iwamoto SJ, Rothman MS, Duan S, Baker JC, Mumm S, Whyte MP (2020) Early-onset Paget's disease of bone in a Mexican family caused by a novel tandem duplication (77dup27) in TNFRSF11A that encodes RANK. Bone 133:115224

    Article  CAS  Google Scholar 

  24. Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP (2008) Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 83:64–76

    Article  CAS  Google Scholar 

  25. Pangrazio A, Cassani B, Guerrini MM, Crockett JC, Marrella V, Zammataro L, Strina D, Schulz A, Schlack C, Kornak U, Mellis DJ (2012) RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations. J Bone Miner Res 27:342–351

    Article  CAS  Google Scholar 

  26. Shamriz O, Shaag A, Yaacov B, NaserEddin A, Weintraub M, Elpeleg O, Stepensky P (2017) The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis. Clin Genet 92:80–85

    Article  CAS  Google Scholar 

  27. Alabdullatif MA, Al Dhaibani MA, Khassawneh MY, El-Hattab AW (2017) Chromosomal microarray in a highly consanguineous population: diagnostic yield, utility of regions of homozygosity, and novel mutations. Clin Genet 91:616–622

    Article  CAS  Google Scholar 

  28. Guo L, Elcioglu NH, Karalar OK, Topkar MO, Wang Z, Sakamoto Y, Matsumoto N, Miyake N, Nishimura G, Ikegawa S (2018) Dysosteosclerosis is also caused by TNFRSF11A mutation. J Hum Genet 63:769–774

    Article  CAS  Google Scholar 

  29. Xue JY, Wang Z, Shinagawa S, Ohashi H, Otomo N, Elcioglu NH, Nakashima T, Nishimura G, Ikegawa S, Guo L (2019) TNFRSF11A-associated dysosteosclerosis: a report of the second case and characterization of the phenotypic spectrum. J Bone Miner Res 34:1873–1879

    Article  CAS  Google Scholar 

  30. Fukumoto S, Matsumoto T (2017) Recent advances in the management of osteoporosis. F1000Research 6:625

    Article  Google Scholar 

  31. Ahern E, Smyth MJ, Dougall WC, Teng MW (2018) Roles of the RANKL-RANK axis in antitumour immunity-implications for therapy. Nat Rev Clin Oncol 15:676–693

    Article  Google Scholar 

  32. Diker-Cohen T, Rosenberg D, Avni T, Shepshelovich D, Tsvetov G, Gafter-Gvili A (2020) Risk for infections during treatment with denosumab for osteoporosis: a systematic review and meta-analysis. J Clin Endocrinol Metab 105:1641–1658

    Article  Google Scholar 

  33. Naot D, Wilson LC, Allgrove J, Adviento E, Piec I, Musson DS, Cundy T, Calder AD (2020) Juvenile Paget's disease with compound heterozygous mutations in TNFRSF11B presenting with recurrent clavicular fractures and a mild skeletal phenotype. Bone 130:115098

    Article  CAS  Google Scholar 

  34. Grasemann C, Schündeln MM, Hövel M, Schweiger B, Bergmann C, Herrmann R, Wieczorek D, Zabel B, Wieland R, Hauffa BP (2013) Effects of RANK-ligand antibody (denosumab) treatment on bone turnover markers in a girl with juvenile Paget's disease. J Clin Endocrinol Metab 98:3121–3126

    Article  CAS  Google Scholar 

  35. Saki F, Karamizadeh Z, Nasirabadi S, Mumm S, McAlister WH, Whyte MP (2013) Juvenile paget’s disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation. J Bone Miner Res 28:1501–1508

    Article  CAS  Google Scholar 

  36. Naot D, Choi A, Musson DS, Simsek Kiper PÖ, Utine GE, Boduroglu K, Peacock M, DiMeglio LA, Cundy T (2014) Novel homozygous mutations in the osteoprotegerin gene TNFRSF11B in two unrelated patients with juvenile Paget’s disease. Bone 68:6–10

    Article  CAS  Google Scholar 

  37. Gottesman GS, Madson KL, McAlister WH, Nenninger A, Wenkert D, Mumm S, Whyte MP (2016) Auricular ossification: a newly recognized feature of osteoprotegerin-deficiency juvenile Paget disease. Am J Med Genet A 170A:978–985

    Article  Google Scholar 

  38. Grasemann C, Unger N, Hövel M, Arweiler-Harbeck D, Herrmann R, Schündeln MM, Müller O, Schweiger B, Lausch E, Meissner T, Kiewert C, Hauffa BP, Shaw NJ (2017) Loss of functional osteoprotegerin: more than a skeletal problem. J Clin Endocrinol Metab 102:210–219

    Article  Google Scholar 

Download references

Acknowledgements

This study is supported by grants from the Japan Society for the Promotion of Science (SI, No. 18H02932) and the Japan Agency For Medical Research and Development (SI, No. 20bm0804006h0104 and 20ek0109486h0001). We thank Mrs. Tomoko Kusadokoro for help in a series of our osteosclerosis studies.

Author information

Authors and Affiliations

  1. Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, 4-6-1 Minato-ku, Tokyo, 108-8639, Japan

    Jing-Yi Xue, Shiro Ikegawa & Long Guo

  2. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Jing-Yi Xue

Authors
  1. Jing-Yi Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiro Ikegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Long Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shiro Ikegawa or Long Guo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 20 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xue, JY., Ikegawa, S. & Guo, L. Genetic disorders associated with the RANKL/OPG/RANK pathway. J Bone Miner Metab 39, 45–53 (2021). https://doi.org/10.1007/s00774-020-01148-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-020-01148-4

Keywords

Search

Navigation