Juvenile Paget's disease (JPD), an autosomal recessive osteopathy, features rapidly remodeling woven bone, osteopenia, fractures, and progressive skeletal deformity that can be fatal by young adult life. Homozygous deletion of the TNFRSF11B gene, encoding osteoprotegerin (OPG), was identified as the cause of JPD in two Navajo families. Previously, a defect in the RANK (receptor activator of nuclear factor ?-B) gene was determined to be the cause of a related disorder, familial expansile osteolysis (FEO). Hence, mutations in genes involved in the OPG/RANKL/RANK/NF-?B signaling pathway are responsible for JPD and related disorders of bone turnover. The long-range goal of this study is to identify other mutations in members of the OPG/RANKL/RANK/NF-?B pathway that cause JPD and related diseases in newly-ascertained patients, and to use in vitro cell modeling systems to assess the downstream effects of these mutations, to elucidate the pathobiology of these disorders.
The Specific Aims of this project are:
Specific Aim 1 : Ascertain and evaluate additional patients worldwide with juvenile Paget's disease (JPD), familial expansile osteolysis (FEO), and related disorders.
Specific Aim 2 : In new patients with JPD, FEO, and related disorders, identify the genetic defects that cause these skeletal diseases.
Specific Aim 3 : Characterize the downstream effects of mutant OPG, RANK, and other members of the OPG/RANKL/RANK/NF-?B signaling pathway on osteoclast formation and action. Additional patients will be ascertained, and evaluated radiographically, biochemically, and molecularly. DNA and RNA samples will be screened for mutations in TNFRSF11B, encoding OPG, TNFRSF11A, encoding RANK, and TNFSF11, encoding RANKL, using PCR and capillary DNA sequencing, and RT-PCR. We will also use a microarray-based copy number analysis to identify potential genomic defects in these patients, and identify new candidate genes. For patients without mutations in the OPG, RANK, or RANKL genes, large-scale Solexa sequencing will be used to search other candidate genes in the OPG/RANKL/RANK/NF-?B signaling pathway for disease-causing mutations, including SQSTM1, VCP, TRAF6, aPKC, NIK, and others. Modulators of RANK signaling will also be examined, including TRAIL, IL-1, MCSF, c-FMS and additional cytokines and their cognate receptors. In vitro osteoclast culture assays will be used to determine downstream effects of mutations on osteoclast formation and function. These studies will further elucidate the genetic bases for JPD, FEO, and related disorders of bone turnover, caused by defects in the OPG/RANKL/RANK/NF-?B signaling pathway, which is critical for osteoclast formation and action.

Public Health Relevance

This project combines clinical evaluation, genetic analysis, and experimental studies for patients and their families with rare bone diseases, including juvenile Paget's disease, familial expansile osteolysis, and related disorders. By understanding the genetic causes and cellular mechanisms of these skeletal diseases, new and better treatments can be developed. The information gained from this study may also be useful for therapy in common bone diseases, such as osteoporosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Mumm, Steven; Huskey, Margaret; Duan, Shenghui et al. (2014) Multicentric carpotarsal osteolysis syndrome is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis. Am J Med Genet A 164A:2287-93
Schafer, Anne L; Mumm, Steven; El-Sayed, Ivan et al. (2014) Panostotic expansile bone disease with massive jaw tumor formation and a novel mutation in the signal peptide of RANK. J Bone Miner Res 29:911-21
Whyte, Michael P; Tau, Cristina; McAlister, William H et al. (2014) Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 68:153-61
Saki, Forough; Karamizadeh, Zohreh; Nasirabadi, Shiva et al. (2013) Juvenile paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation. J Bone Miner Res 28:1501-8
Whyte, Michael P; Totty, William G; Novack, Deborah V et al. (2011) Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFýý1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand. J Bone Miner Res 26:920-33
Whyte, Michael P; Wenkert, Deborah; McAlister, William H et al. (2010) Dysosteosclerosis presents as an "osteoclast-poor" form of osteopetrosis: comprehensive investigation of a 3-year-old girl and literature review. J Bone Miner Res 25:2527-39