臨床整形外科48巻8号

2013年08月発行

最新基礎科学/知っておきたい

Nogginの骨・関節形成における機能と病態への関与

著者： 二藤彰¹

所属機関： ¹鶴見大学歯学部薬理学

ページ範囲：P.764 - P.769

■はじめに

　Nogginはもともと発生初期の頭尾軸の向きを決める分子として(“noggin”は頭という意味)，20年ほど前にアフリカツメガエルで発見，同定された分子である³⁵⁾．Nogginが発見されるより少し前に分子の構造が同定されたBMP(bone morphogenetic protein：骨形成因子)も，骨形成のみならず，発生初期の軸を決めるのに重要であることが示された¹¹⁾．その後，BMPとNogginが作用において逆であるのみならず，生化学的にも結合阻害する分子であることが示され，BMPに対する生体内の阻害物質である可能性が示された⁴⁵⁾．そのBMPとNogginの拮抗関係が骨形成過程でも予想され，実際BMPによる骨形成促進作用が，Nogginによって阻害されることが示された³⁾．

　その後，Nogginのみならず，他にも多くのBMP阻害分子sclerostin(SOST)，twisted gastrulation(Tsg)，chordin，gremlin，follistatin，Dan，Dante，PRDC(protein related to Dan and Dante)などが報告された^17,25,28,39)．そのうち，ヒトで疾病の原因遺伝子として遺伝子変異が報告されたのは，nogginとsclerostinだけである¹⁸⁾．

　本稿ではNogginの骨系統疾患との関連についての最新の知見を紹介するとともに，そこから推測されうるNogginの疾病への関与について考察したい．

参考文献

1) Athanasakis E, Biarnés X, Bonati MT, et al:Identification of a new mutation (L46P) in the human NOG gene in an Italian patient with symphalangism syndrome. Mol Syndromol 3:21-24, 2012

2) Brown DJ, Kim TB, Petty EM, et al:Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet 71:618-624, 2002

3) Brunet LJ, McMahon JA, McMahon AP, Harland RM:Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280:1455-1457, 1998

4) Canalis E, Brunet LJ, Parker K, et al:Conditional inactivation of noggin in the postnatal skeleton causes osteopenia. Endocrinology 153:1616-1626, 2012

5) Dawson K, Seeman P, Sebald E, et al:GDF5 is a second locus for multiple-synostosis syndrome. Am J Hum Genet 78:708-712, 2006

6) Debeer P, Baten E, Huysmans C, et al:A novel NOG mutation Pro37Arg in a family with tarsal and carpal synostoses. Am J Med Genet A 128:439-440, 2004

7) Debeer P, Huysmans C, Van de Ven WJ, et al:Carpal and tarsal synostoses and transverse reduction defects of the toes in two brothers heterozygous for a double de novo NOGGIN mutation. Am J Med Genet A 134:318-320, 2005

8) Dixon ME, Armstrong P, Stevens DB, et al:Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med 3:349-353, 2001

9) Emery SB, Meyer A, Miller L, et al:Otosclerosis or congenital stapes ankylosis? The diagnostic role of genetic analysis. Otol Neurotol 30:1204, 2009

10) Gong Y, Krakow D, Marcelino J, et al:Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 21:302-304, 1999

11) Graff JM:Embryonic patterning:to BMP or not to BMP, that is the question. Cell 89:171-174, 1997

12) Groppe J, Greenwald J, Wiater E, et al:Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420:636-642, 2002

13) Groppe J, Greenwald J, Wiater E, et al:Structural basis of BMP signaling inhibition by Noggin, a novel twelve-membered cystine knot protein. J Bone Joint Surg Am 85 Suppl 3:52-58, 2003

14) Herrmann J:Symphalangism and brachydactyly syndrome:report of the WL symphalangism-brachydactyly syndrome:review of literature and classification. Birth Defects Orig Artic Ser 10:23-53, 1974

15) Hirshoren N, Gross M, Banin E, et al:P35S mutation in the NOG gene associated with Teunissen-Cremers syndrome and features of multiple NOG joint-fusion syndromes. Eur J Med Genet 51:351-357, 2008

16) Hwang CH, Wu DK:Noggin heterozygous mice:an animal model for congenital conductive hearing loss in humans. Hum Mol Genet 17:844-853, 2008

17) Ideno H, Takanabe R, Shimada A, et al:Protein related to DAN and cerberus (PRDC) inhibits osteoblastic differentiation and its suppression promotes osteogenesis in vitro. Exp Cell Res 315:474-484, 2009

18) Janssens K, Van Hul W:Molecular genetics of too much bone. Hum Mol Genet 11:2385-2393, 2002

19) Kosaki K, Sato S, Hasegawa T, et al:Premature ovarian failure in a female with proximal symphalangism and Noggin mutation. Fertility and sterility 81:1137-1139, 2004

20) Lehmann K, Seemann P, Silan F, et al:A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Am J Hum Genet 81:388-396, 2007

21) Mangino M, Flex E, Digilio MC, et al:Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism. Hum Mutat 19:308-308, 2002

22) Marcelino J, Sciortino CM, Romero MF, et al:Human disease-causing NOG missense mutations:effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. Proc Natl Acad Sci USA 98:11353-11358, 2001

23) Nifuji A, Kellermann O, Noda M:Noggin expression in a mesodermal pluripotent cell line C1 and its regulation by BMP. J Cell Biochem 73:437-444, 1999

24) Nifuji A, Noda M:Coordinated expression of noggin and bone morphogenetic proteins (BMPs) during early skeletogenesis and induction of noggin expression by BMP-7．J Bone Miner Res 14:2057-2066, 1999

25) Ohyama Y, Nifuji A, Maeda Y, et al:Spaciotemporal association and bone morphogenetic protein regulation of sclerostin and osterix expression during embryonic osteogenesis. Endocrinology 145:4685-4692, 2004

26) Oldridge M, Fortuna AM, Maringa M, et al:Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 24:275-278, 2000

27) Oxley CD, Rashid R, Goudie DR, et al:Growth and skeletal development in families with NOGGIN gene mutations. Horm Res 69:221-226, 2008

28) Petryk A, Anderson RM, Jarcho MP, et al:The mammalian twisted gastrulation gene functions in foregut and craniofacial development. Dev Biol 267:374-386, 2004

29) Potti TA, Petty EM, Lesperance MM:A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term:NOG-related-symphalangism spectrum disorder (NOG-SSD). Hum Mutat 32:877-886, 2011

30) Rudnik-Schöneborn S, Takahashi T, Busse S, et al:Facioaudiosymphalangism syndrome and growth acceleration associated with a heterozygous NOG mutation. Am J Med Genet A 152A:1540-1544, 2010

31) Sawant A, Chanda D, Isayeva T, et al:Noggin is novel inducer of mesenchymal stem cell adipogenesis:implications for bone health and obesity. J Biol Chem 287:12241-12249, 2012

32) Schwaerzer GK, Hiepen C, Schrewe H, et al:New insights into the molecular mechanism of multiple synostoses syndrome (SYNS):Mutation within the GDF5 knuckle epitope causes noggin-resistance. J Bone Miner Res 27:429-442, 2012

33) Seemann P, Mundlos S:The tale of FOP, NOGGIN and myristoylation:no data, no proof!. Genet Couns 19:353, 2008

34) Sémonin O, Fontaine K, Daviaud C, et al:Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva. Am J Med Genet 102:314-317, 2001

35) Smith WC, Harland RM:Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 70:829-840, 1992

36) Stafford DA, Brunet LJ, Khokha MK, et al:Cooperative activity of noggin and gremlin 1 in axial skeleton development. Development 138:1005-1014, 2011

37) Takahashi T, Takahashi I, Komatsu M, et al:Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Genet 60:447-451, 2001

38) Thomeer HG, Admiraal RJ, Hoefsloot L, et al:Proximal symphalangism, hyperopia, conductive hearing impairment, and the NOG gene:2 new mutations. Otol Neurotol 32:632-638, 2011

39) Topol LZ, Bardot B, Zhang Q, et al:Biosynthesis, post-translation modification, and functional characterization of Drm/Gremlin. J Biol Chem 275:8785-8793, 2000

40) Tylzanowski P, Mebis L, Luyten FP:The Noggin null mouse phenotype is strain dependent and haploinsufficiency leads to skeletal defects. Dev Dyn 235:1599-1607, 2006

41) Usami S, Abe S, Nishio S, et al:Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis. Clin Genet 82:514-520, 2012

42) van den Ende JJ, Mattelaer P, Declau F, et al:The facio-audio-symphalangism syndrome in a four generation family with a nonsense mutation in the NOG-gene. Clin Dysmorphol 14:73-80, 2005

43) Warman ML, Cormier-Daire V, Hall C, et al:Nosology and classification of genetic skeletal disorders:2010 revision. Am J Med Genet A 155A:943-968, 2011

44) Weekamp HH, Kremer H, Hoefsloot LH, et al:Teunissen-Cremers syndrome:a clinical, surgical, and genetic report. Otol Neurotol 26:38-51, 2005

45) Zimmerman LB, De Jesús-Escobar JM, Harland RM:The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4．Cell 86:599-606, 1996