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Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 3/2018

01-06-2018 | Genetics (M Johnson and S Ralston, Section Editors)

Human Genetics of Sclerosing Bone Disorders

Authors: Raphaël De Ridder, Eveline Boudin, Geert Mortier, Wim Van Hul

Published in: Current Osteoporosis Reports | Issue 3/2018

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Abstract

Purpose of Review

The group of sclerosing bone disorders encompasses a variety of disorders all marked by increased bone mass. In this review, we give an overview of the genetic causes of this heterogeneous group of disorders and briefly touch upon the value of these findings for the development of novel therapeutic agents.

Recent Findings

Advances in the next-generation sequencing technologies are accelerating the molecular dissection of the pathogenic mechanisms underlying skeletal dysplasias.

Summary

Throughout the years, the genetic cause of these disorders has been extensively studied which resulted in the identification of a variety of disease-causing genes and pathways that are involved in bone formation by osteoblasts, bone resorption by osteoclasts, or both processes. Due to this rapidly increasing knowledge, the insights into the regulatory mechanisms of bone metabolism are continuously improving resulting in the identification of novel therapeutic targets for disorders with reduced bone mass and increased bone fragility.
Literature
1.
2.
3.
4.
5.
6.
7.
8.
Cleiren E, Benichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, et al. Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet. 2001;10(25):2861–7.PubMedCrossRef
9.
10.
Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. 2001;104(2):205–15.PubMedCrossRef
11.
Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, et al. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet. 2000;9(13):2059–63.PubMedCrossRef
12.
13.
14.
15.
Smahi A, Courtois G, Rabia SH, Doffinger R, Bodemer C, Munnich A, et al. The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet. 2002;11(20):2371–5.PubMedCrossRef
16.
17.
18.
19.
20.
21.
Marks SC Jr. Osteopetrosis—multiple pathways for the interception of osteoclast function. Appl Pathol. 1987;5(3):172–83.PubMed
22.
23.
Sugiura Y, Yamada Y, Ko J. Pycnodysostosis in Japan: report of six cases and a review of Japaneses literature. Birth Defects Orig Artic Ser. 1974;10(12):78–98.PubMed
24.
Maroteaux P, Lamy M. Pyknodysostosis. Presse Med. 1962;70:999–1002.PubMed
25.
26.
Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996;273(5279):1236–8.PubMedCrossRef
27.
Bromme D, Okamoto K, Wang BB, Biroc S. Human cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts. Functional expression of human cathepsin O2 in Spodoptera frugiperda and characterization of the enzyme. J Biol Chem. 1996;271(4):2126–32.PubMedCrossRef
28.
29.
30.
Shi GP, Chapman HA, Bhairi SM, DeLeeuw C, Reddy VY, Weiss SJ. Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. FEBS Lett. 1995;357(2):129–34.PubMedCrossRef
31.
Everts V, Aronson DC, Beertsen W. Phagocytosis of bone collagen by osteoclasts in two cases of pycnodysostosis. Calcif Tissue Int. 1985;37(1):25–31.PubMedCrossRef
32.
Nishimura G, Kozlowski K. Osteosclerotic metaphyseal dysplasia. Pediatr Radiol. 1993;23(6):450–2.PubMedCrossRef
33.
34.
35.
Balemans W, Van Hul W. Human genetics of SOST. J Musculoskelet Neuronal Interact. 2006;6(4):355–6.PubMed
36.
Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39(2):91–7.PubMedPubMedCentralCrossRef
37.
38.
39.
Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10(5):537–43.PubMedCrossRef
40.
Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68(3):577–89.PubMedPubMedCentralCrossRef
41.
42.
• Fijalkowski I, Geets E, Steenackers E, Van Hoof V, Ramos FJ, Mortier G, et al. A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone. J Bone Miner Res. 2016;31(4):874–81. https://​doi.​org/​10.​1002/​jbmr.​2782. In this study, the authors delivered evidence for the functional implications of mutations in the cavity of the third b-propeller domain in the pathogenesis of sclerosteosis. PubMedCrossRef
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
Hurt RL. Osteopathia striata-Voorhoeve’s disease: report of a case presenting the features of osteopathia striata and osteopetrosis. J Bone Joint Surg Br. 1953;35-B(1):89–96.PubMedCrossRef
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
• Chen IP, Luxmi R, Kanaujiya J, Hao Z, Reichenberger EJ. Craniometaphyseal dysplasia mutations in ANKH negatively affect human induced pluripotent stem cell differentiation into osteoclasts. Stem Cell Rep. 2017;9(5):1369–76. https://​doi.​org/​10.​1016/​j.​stemcr.​2017.​09.​016. This study explores the use of hiPSCs in in vitro functional analyses of osteoclast biology and offers a new tool for investigating molecular mechanisms in diseases as demonstrated by the results on ANKH mutations to study craniometaphyseal dysplasia. CrossRef
70.
71.
72.
Ya J, Erdtsieck-Ernste EB, de Boer PA, van Kempen MJ, Jongsma H, Gros D, et al. Heart defects in connexin43-deficient mice. Circ Res. 1998;82(3):360–6.PubMedCrossRef
73.
Reaume AG, de Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC, et al. Cardiac malformation in neonatal mice lacking connexin43. Science. 1995;267(5205):1831–4.PubMedCrossRef
74.
Lecanda F, Warlow PM, Sheikh S, Furlan F, Steinberg TH, Civitelli R. Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol. 2000;151(4):931–44.PubMedPubMedCentralCrossRef
75.
76.
77.
• Moorer MC, Hebert C, Tomlinson RE, Iyer SR, Chason M, Stains JP. Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation. J Cell Sci. 2017;130(3):531–40. https://​doi.​org/​10.​1242/​jcs.​197285. The results reported in this work expand on the knowledge on connexin 43 in the regulation of cell function and bone acquisition using a truncated connexin 43 mouse model. PubMedPubMedCentralCrossRef
78.
79.
80.
81.
82.
83.
84.
Whyte MP, Totty WG, Novack DV, Zhang X, Wenkert D, Mumm S. Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFbeta1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand. J Bone Miner Res. 2011;26(5):920–33. https://​doi.​org/​10.​1002/​jbmr.​283.PubMedCrossRef
85.
Nishimura G, Nishimura H, Tanaka Y, Makita Y, Ikegawa S, Ghadami M, et al. Camurati-Engelmann disease type II: progressive diaphyseal dysplasia with striations of the bones. Am J Med Genet. 2002;107(1):5–11.PubMedCrossRef
86.
87.
88.
89.
Price JA, Wright JT, Kula K, Bowden DW, Hart TC. A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families. J Med Genet. 1998;35(10):825–8.PubMedPubMedCentralCrossRef
90.
Price JA, Bowden DW, Wright JT, Pettenati MJ, Hart TC. Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum Mol Genet. 1998;7(3):563–9.PubMedCrossRef
91.
92.
Lenz WD, Majewski F. A generalized disorders of the connective tissues with progeria, choanal atresia, symphalangism, hypoplasia of dentine and craniodiaphyseal hypostosis. Birth Defects Orig Artic Ser. 1974;10(12):133–6.PubMed
93.
Majewski F. Lenz-Majewski hyperostotic dwarfism: reexamination of the original patient. Am J Med Genet. 2000;93(4):335–8.PubMedCrossRef
94.
95.
Wattanasirichaigoon D, Visudtibhan A, Jaovisidha S, Laothamatas J, Chunharas A. Expanding the phenotypic spectrum of Lenz-Majewski syndrome: facial palsy, cleft palate and hydrocephalus. Clin Dysmorphol. 2004;13(3):137–42.PubMedCrossRef
96.
97.
98.
99.
Mahbouba J, Mondher G, Amira M, Walid M, Naceur B. Osteopoikilosi: a rare cause of bone pain. Caspian J Intern Med. 2015;6(3):177–9.PubMedPubMedCentral
100.
101.
102.
103.
104.
105.
106.
107.
Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, et al. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet. 2002;11(22):2735–9.PubMedCrossRef
108.
109.
110.
111.
112.
• Vallet M, Soares DC, Wani S, Sophocleous A, Warner J, Salter DM, et al. Targeted sequencing of the Paget’s disease associated 14q32 locus identifies several missense coding variants in RIN3 that predispose to Paget’s disease of bone. Hum Mol Genet. 2015;24(11):3286–95. https://​doi.​org/​10.​1093/​hmg/​ddv068. The sequencing effort reported in this study was the first to look into the genetic variation in the RIN3 gene in the context of human disease. This gene has been implicated in bone research following GWAS on Paget’s disease and bone and BMD. PubMedPubMedCentralCrossRef
113.
114.
115.
Watts GDJ, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet. 2004;36:377–81. https://​doi.​org/​10.​1038/​ng1332 https://www.nature.com/articles/ng1332#supplementary-information.
116.
117.
118.
119.
120.
121.
122.
123.
124.
• Lu B, Jiao Y, Wang Y, Dong J, Wei M, Cui B, et al. A FKBP5 mutation is associated with Paget’s disease of bone and enhances osteoclastogenesis. Exp Mol Med. 2017;49(5):e336. https://​doi.​org/​10.​1038/​emm.​2017.​64. Using WES, the authors identified mutations in a previously unreported gene for Paget’s disease of bone and deliver functional evidence for its potential involvement. PubMedPubMedCentralCrossRef
125.
126.
Divisato G, di Carlo FS, Petrillo N, Esposito T, Gianfrancesco F. ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget’s disease of bone. Clin Genet. 2018; https://​doi.​org/​10.​1111/​cge.​13247.
127.
128.
129.
130.
131.
Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, et al. A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet. 2002;11(18):2119–27.PubMedCrossRef
132.
133.
134.
135.
136.
Donath J, Speer G, Kosa JP, Arvai K, Balla B, Juhasz P, et al. Polymorphisms of CSF1 and TM7SF4 genes in a case of mild juvenile Paget’s disease found using next-generation sequencing. Croat Med J. 2015;56(2):145–51.PubMedPubMedCentralCrossRef
137.
Troen BR. The role of cathepsin K in normal bone resorption. Drug News Perspect. 2004;17(1):19–28.PubMedCrossRef
138.
139.
• Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417–27. https://​doi.​org/​10.​1056/​NEJMoa1708322. The authors demonstrate that preceeding alendronate treatment with romosozumab administration decreases the risk of fracture more significantly than that of alendronate treatment alone in postmenopausal patients with high risk of fracture. PubMedCrossRef
140.
Metadata
Title
Human Genetics of Sclerosing Bone Disorders
Authors
Raphaël De Ridder
Eveline Boudin
Geert Mortier
Wim Van Hul
Publication date
01-06-2018
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 3/2018
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-018-0439-7

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