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Current Osteoporosis Reports

Erschienen in:

02.05.2017 | Rare Bone Diseases (C Langman and E Shore, Section Editors)

Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments

verfasst von: Maurizio Pacifici

Erschienen in: Current Osteoporosis Reports | Ausgabe 3/2017

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Abstract

Purpose of Review

Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention.

Recent Findings

Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends.

Summary

HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.

Luckert Wicklund CL, Pauli RM, Johnson DR, Hecht JT. Natural history of hereditary multiple exostoses. Am J Med Genet. 1995;55:43–6.CrossRef

Schmale GA, Conrad EU, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am. 1994;76:986–92.CrossRefPubMed

Solomon L. Hereditary multiple exostosis. J Bone Joint Surg. 1963;45B:292–304.

Stieber JR, Dormans JP. Manifestations of hereditary multiple exostoses. J Am Acad Orthop Surg. 2005;13:110–20.CrossRefPubMed

Uchida K, Kurihara Y, Sekiguchi S, Doi Y, Matsuda K, Miyanaga M, et al. Spontaneous haemothorax caused by costal exostosis. Eur Respir J. 1997;10:735–6.PubMed

Dormans JP. Pediatric orthopaedics: core knowledge in orthopaedics. Philadelphia: Elsevier Mosby; 2005.

Jones KB. Glycobiology and the growth plate: current concepts in multiple hereditary exostoses. J Pediatr Orthop. 2011;31:577–86.CrossRefPubMedPubMedCentral

Porter DE, Lonie L, Fraser M, Dobson-Stone C, Porter JR, Monaco AP, et al. Severity of disease and risk in malignant change in hereditary multiple exostoses. J Bone Joint Surg Br. 2004;86:1041–6.CrossRefPubMed

Porter DE, Simpson AHRW. The neoplastic pathogenesis of solitary and multiple osteochondromas. J Pathol. 1999;188:119–25.CrossRefPubMed

10.

Ahn J, Ludecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, et al. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet. 1995;11:137–43.CrossRefPubMed

11.

Cheung PK, McCormick C, Crawford BE, Esko JD, Tufaro F, Duncan G. Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity. Am J Hum Genet. 2001;69:55–66.CrossRefPubMedPubMedCentral

12.

Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner H. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosome 11 and 8. Am J Hum Genet. 1995;56:1125–31.PubMedPubMedCentral

13.

Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat. 2000;15:220–7.CrossRefPubMed

14.

Bishop JR, Schuksz M, Esko JD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature. 2007;446:1030–7.CrossRefPubMed

15.

Esko JD, Selleck SB. Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem. 2002;71:435–71.CrossRefPubMed

16.

McCormick C, Duncan G, Goutsos KT, Tufaro F. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi complex and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci U S A. 2000;97:668–73.CrossRefPubMedPubMedCentral

17.

Anower-E-Khuda MF, Matsumoto K, Habuchi H, Morita H, Yokochi T, Shimizu K, et al. Glycosaminoglycans in the blood of hereditary multiple exostoses patients: half reduction of heparan sulfate to chondroitin sulfate ratio and the possible diagnostic application. Glycobiology. 2013;23:865–76.CrossRefPubMed

18.

•• Mooij HL, BernelotMoens SJ, Gordts PL, Stanford KI, Foley EM, van den Boogert MA, et al. Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans. J Lipid Res. 2015;56:665–73. This paper shows for the first time that EXT1 heterozygosity itself can affect nonskeletal functions in HME patients. CrossRefPubMedPubMedCentral

19.

Huegel J, Sgariglia F, Enomoto-Iwamoto M, Koyama E, Dormans JP, Pacifici M. Heparan sulfate in skeletal development, growth, and pathology: the case of hereditary multiple exostoses. Dev Dyn. 2013;242:1021–32.CrossRefPubMedPubMedCentral

20.

Knudson A. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820–3.CrossRefPubMedPubMedCentral

21.

Bovee JV, Cleton-Jansen A-M, Wuyts W, Caethoven G, Taminiau AH, Bakker E, et al. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcoma. Am J Hum Genet. 1999;65:689–98.CrossRefPubMedPubMedCentral

22.

Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, van Dekken H, et al. The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. J Natl Cancer Inst. 2007;99:396–406.CrossRefPubMed

23.

Reijnders CM, Waaijer CJ, Hamilton A, Buddingh EP, Dijkstra SP, Ham J, et al. No haploinsufficiency but loss of heterozygosity for EXT in multiple osteochondromas. Am J Path. 2010;177:1946–57.CrossRefPubMedPubMedCentral

24.

Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs MB, et al. Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Cell Motil Cytoskeleton. 2001;48:149–62.CrossRefPubMed

25.

Hall CR, Cole WG, Haynes R, Hecht JT. Reevaluation of a genetic model for the development of exostoses in hereditary multiple exostosis. Am J Med Genet. 2002;112:1–5.CrossRefPubMed

26.

Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG, et al. Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat. 2009;30:1620–7.CrossRefPubMed

27.

Zuntini M, Pedrini E, Parra A, Sgariglia F, Gentile FV, Pandolfi M, et al. Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation. Oncogene. 2010;29:3827–34.CrossRefPubMed

28.

Stickens D, Zak BM, Rougier N, Esko JD, Werb Z. Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development. 2005;132:5055–68.CrossRefPubMedPubMedCentral

29.

•• Zak BM, Schuksz M, Koyama E, Mundy C, Wells DE, Yamaguchi Y, et al. Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones. Bone. 2011;48:979–87. This paper shows for the first time that compound heterozygous Ext mutations are sufficient to cause an HME-like phenotype in mice. CrossRefPubMedPubMedCentral

30.

•• Jones KB, Piombo V, Searby C, Kurriger G, Yang B, Grabellus F, et al. A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proc Natl Acad Sci U S A. 2010;107:2054–9. This paper has provided the most direct evidence to date that stocastic loss of Ext1 alleles in a few cells is sufficient to elicit osteochondormal formation. CrossRefPubMedPubMedCentral

31.

•• Matsumoto K, Irie F, Mackem S, Yamaguchi Y. A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Proc Natl Acad Sci U S A. 2010;107:10932–7. This concurrent paper has provided the most direct evidence to date that stocastic loss of Ext1 alleles in a few cells is sufficient to elicit osteochondormal formation. CrossRefPubMedPubMedCentral

32.

Sgariglia F, Candela ME, Huegel J, Jacenko O, Koyama E, Yamaguchi Y, et al. Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice. Bone. 2013;57:220–31.CrossRefPubMedPubMedCentral

33.

Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate proteoglycans. Cold Spring Harb Prospect Biol. 2011;3:a004952.

34.

Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson CP. Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science. 2001;293:1663–6.CrossRefPubMed

35.

Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD. Cloning and characterization of two extracellular heparin-degrading endosulfatases in mouse and human. J Biol Chem. 2002;277:49175–85.CrossRefPubMedPubMedCentral

36.

Billings PC, Pacifici M. Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries. Connect Tissue Res. 2015;56:272–80.CrossRefPubMedPubMedCentral

37.

Lin X. Functions of heparan sulfate proteoglycans in cell signaling during development. Development. 2004;131:6009–21.CrossRefPubMed

38.

Xu D, Esko JD. Demystifying heparan sulfate-protein interactions. Annu Rev Biochem. 2014;83:129–57.CrossRefPubMed

39.

Koziel L, Kunath M, Kelly OG, Vortkamp A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell. 2004;6:801–13.CrossRefPubMed

40.

Huegel J, Mundy C, Sgariglia F, Nygren P, Billings PC, Yamaguchi Y, et al. Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in hereditary multiple exostoses. Dev Biol. 2013;377:100–12.CrossRefPubMedPubMedCentral

41.

Clement ND, Duckworth AD, Baker AD, Porter DE. Skeletal growth patterns in hereditary multiple exostoses: a natural history. J Pediatr Orthop. 2012;B21:150–4.CrossRef

42.

Clement ND, Porter DE. Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender. Scottish Med J. 2014;59:34–44.CrossRef

43.

Porter DE, Benson MK, Hosney GA. The hip in hereditary multiple exostoses. J Bone Joint Surg Br. 2001;83:988–95.CrossRefPubMed

44.

Wang YZ, Park K-W, Oh C-S, Ahn Y-S, Kang Q-L, Jung ST, et al. Developmental pattern of the hip in patients with hereditary multiple exostoses. BMC Musculoskelet Disord. 2015;16:54.CrossRefPubMedPubMedCentral

45.

Roach JW, Klatt JWB, Faulkner ND. Involvement of the spine in patients with multiple hereditary exostoses. J Bone Joint Surg. 2009;91:1942–8.CrossRefPubMed

46.

• Matsumoto Y, Matsumoto K, Harimaya K, Okada S, Doi T, Iwamoto Y. Scoliosis in patients with multiple hereditary exostoses. Eur Spine J. 2015;24:1568–73. This paper is the first to suggest that scoliosis may be more pervasive than previously thought in HME patients. CrossRefPubMed

47.

Felix NA, Mazur JM, Loveless EA. Acetabular dysplasia associated with hereditary multiple exostoses. A case report. J Bone Joint Surg Br. 2000;82:555–7.CrossRefPubMed

48.

Hosalkar H, Greenberg J, Gaugler RL, Garg S, Dormans JP. Abnormal scarring with keloid formation after osteochondroma excision in children with multiple hereditary exostoses. J Pediatr Orthop. 2007;27:333–7.CrossRefPubMed

49.

•• Goud AL, de Lange J, Scholtes VA, Bulstra SK, Ham SJ. Pain, physical and social functioning, and quality of life in individuals with multiple hereditary exostoses in The Netherlands: a national cohort study. J Bone Joint Surg Am. 2012;94:1013–20. This paper represents one of the most extensive and attentive analysis of physicial, social and personal difficulties experienced by HME patients. CrossRefPubMed

50.

Chhina H, Davis J, Alvarez CM. Health-related quality of life in people with hereditary multiple exostoses. J Pediatr Orthopaedics. 2012;32:210–4.CrossRef

51.

Arkader A. Multiple hereditary exostoses: its burden on childhood and beyond. J Bone Joint Surg. 2012;94:e81.CrossRefPubMed

52.

Hays RD, Morales LS. The RAND-36 measure of health-related quality of life. Annu Med. 2001;33:350–7.CrossRef

53.

Ashraf A, Larson AN, Ferski G, Mielke CH, Wetjen NM, Guidera KJ. Spinal stenosis frequent in children with multiple hereditary exostoses. J Child Orthop. 2013;7:183–94.CrossRefPubMedPubMedCentral

54.

Oestreich AT, Huslig EL. Hereditary multiple exostosis: another etiology of short leg and scoliosis. J Manip Physiol Ther. 1985;8:267–9.

55.

King HA, Moe JH, Bradford DS, Winter RB. The selection of fusion levels in thoracic idiopathic scoliosis. J Bone Joint Surg Am. 1983;65:1302–12.CrossRefPubMed

56.

Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem. 1998;273:26265–8.CrossRefPubMed

57.

McCormick C, Leduc Y, Martindale D, Mattison K, Esford L, Dyer A, et al. The putative tumor suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet. 1998;19:158–61.CrossRefPubMed

58.

Busse-Wicher M, Wicher KB, Kusche-Gullberg M. The exostosin family: proteins with many functions. Matrix Biol. 2014;35:25–33.CrossRefPubMed

59.

Alvarez C, De Vera MA, Heslip TR, Casey B. Evaluation of the anatomical burden of patients with hereditary multiple exostoses. Clin Orth Relat Res. 2007;462:73–9.CrossRef

60.

Alvarez C, Tredwell S, De Vera M, Hayden M. The genotype-phenotype correlation of hereditary multiple exostoses. Clin Genet. 2006;70:122–30.CrossRefPubMed

61.

Pedrini E, Jennes I, Tremosini M, Milanesi A, Mordenti M, Parra A, et al. Genotype-phenotype correlation study in 529 patients with hereditary multiple exostoses: identification of “protective” and “risk” factors. J Bone Joint Surg. 2011;93:2294–302.CrossRefPubMed

62.

Ishimaru D, Gotch M, Takayama S, Kosaki R, Matsumoto Y, Narimatsu H, et al. Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas. BMC Genet. 2016;17:52.CrossRefPubMedPubMedCentral

63.

Sarrion P, Sangorrin A, Urreizti R, Delgado A, Artuch R, Mantorell L, et al. Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas. Sci Rep. 2013;3:1346.CrossRefPubMedPubMedCentral

64.

Jamsheer M, Socha M, Sowinska-Seidler A, Telega K, Trzeciak T, Latos-Bielenska A. Mutational screening of EXT1 and EXT2 genes in Polish patients with hereditary multiple exostoses. J Appl Genet. 2014;55:183–8.CrossRefPubMedPubMedCentral

65.

Ciavarella M, Coco M, Baorda F, Stanziale P, Chetta M, Bisceglia L, et al. 20 novel point mutations and one large deletion in EXT1 and EXT2 genes: report of diagnostic screening in a large Italian cohort of patients affected by hereditary multiple exostosis. Gene. 2013;515:339–48.CrossRefPubMed

66.

Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol. 1996;122:135–40.CrossRefPubMed

67.

Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FW, et al. Association of the autoimmune disease scherederma with an immunologic response to cancer. Science. 2014;343:152–7.CrossRefPubMed

68.

•• Irie F, Badie-Mahdavi H, Yamaguchi Y. Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. Proc Natl Acad Sci U S A. 2012;109:5052–6. This paper is the first to show that conditional ablation of Ext1 in brain cells can cause symptoms of autism in mice. CrossRefPubMedPubMedCentral

69.

•• Cousminer DL, Arkader A, Voight BF, Pacifici M, Grant SFA. Assessing the general population frequency of rare coding variants in the EXT1 and EXT2 genes previously implicated in hereditary multiple exostoses. Bone. 2016;92:196–200. This paper is the first to suggest that some EXT missense mutations previously linked to HME may actually be variants with little if any pathogenic relevance. CrossRefPubMed

70.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.CrossRefPubMedPubMedCentral

71.

Hecht JT, Hayes E, Haynes R, Cole GC, Long RJ, Farach-Carson MC, et al. Differentiation-induced loss of heparan sulfate in human exostosis derived chondrocytes. Differentiation. 2005;73:212–21.CrossRefPubMed

72.

Colnot C, Lu C, Hu D, Helms JA. Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development. Dev Biol. 2004;269:55–69.CrossRefPubMed

73.

Lam KP, Rajewsky K. Rapid elimination of mature autoreactive B cells demonstrated by Cre-induced change in B cell antigen receptor specificity in vivo. Proc Natl Acad Sci U S A. 1998;95:13171–5.CrossRefPubMedPubMedCentral

74.

Ono N, Ono W, Nagasawa T, Kronenberg HM. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol. 2014;16:1157–67.CrossRefPubMedPubMedCentral

75.

Maes C, Kobayashi A, Kronenberg HM. A novel transgenic mous emodel to stuudy the osteoblast lineage in vivo. Ann N Y Acad Sci. 2007;1116:1490164.CrossRef

76.

Nakamura E, Nguyen M-T, Mackem S. Kinetics of tamoxifen-regulated Cre activity in mice using a cartilage-specific CreER^T to assay temporal activity windows along the proximodistal limb skeleton. Dev Dyn. 2006;235:2603–12.CrossRefPubMed

77.

Schuksz M, Fuster MM, Brown JR, Crawford BE, Ditto DP, Lawrence R, et al. Surfen, a small molecule antagonist of heparan sulfate. Proc Natl Acad Sci U S A. 2008;105:13075–80.CrossRefPubMedPubMedCentral

78.

Salazar VS, Gamer LW, Rosen V. BMP signaling in skeletal development, disease and repair. Nat Rev Endocrinol. 2016;12:203–21.CrossRefPubMed

79.

Buckland RA, Collinson JM, Graham E, Davidson DR, Hill RE. Antagonistic effects of FGF4 on BMP induction of apoptosis and chondrogenesis in the chick limb bud. Mech Dev. 1998;71:143–50.CrossRefPubMed

80.

Ornitz DM, Marie PJ. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 2015;29:1463–86.CrossRefPubMedPubMedCentral

81.

Yoon BS, Pogue R, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, et al. BMPs regulate multiple aspects of growth plate chondrogenesis through opposing actions of FGF pathways. Development. 2006;133:4667–78.CrossRefPubMed

82.

Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR. Cloning of mammalian heparanase: an important enzyme in tumor invasion and metastasis. Nat Med. 1999;5:183–7.CrossRef

83.

Zetser A, Bashenko Y, Miao HQ, Vlodavsky I, Ilan N. Heparanase affects adhesive and tumorigenic potential of human glioma cells. Cancer Res. 2003;63:7733–41.PubMed

84.

Quiros RM, Rao G, Plate J, Harris JE, Brunn GJ, Platt JL, et al. Elevated serum heparanase-1 levels in patients with pancreatic carcinoma are associated with poor survival. Cancer. 2006;106:532–40.CrossRefPubMed

85.

•• Trebicz-Geffen M, Robinson D, Evron Z, Glaser T, Fridkin M, Kollander Y, et al. The molecular and cellular basis of exostosis formation in hereditary multiple exostoses. Int J Exp Path. 2008;89:321–31. This paper is the first to show that heparanase is up-regulated in osteochondromas from HME patients. CrossRef

86.

•• Huegel J, Enomoto-Iwamoto M, Sgariglia F, Koyama E, Pacifici M. Heparanase stimulates chondrogenesis and is up-regulated in human ectopic cartilage. A mechanism possibly involved in hereditary multiple exostoses. Am J Path. 2015;185:1676–85. This paper verifies that heparanase is up-regulated in osteochondromas from HME patients and is the first to show that human heparanase stimulates chondrogenesis while a heparanase inhibitor inhibits it, indicating that this enzyme could be a therapeutic target. CrossRefPubMedPubMedCentral

87.

Ritchie JP, Ramani VC, Ren Y, Naggi A, Torri G, Casu B, et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. Clin Cancer Res. 2011;17:1382–93.CrossRefPubMedPubMedCentral

88.

Matsumoto Y, Matsumoto K, Irie F, Fukushi J-I, Stallcup WB, Yamaguchi Y. Conditional ablation of the heparan sulfate-synthesizing enzyme Ext1 leads to dysregulation of bone morphogenetic protein signaling and severe skeletal defects. J Biol Chem. 2010;285:19227–34.CrossRefPubMedPubMedCentral

89.

Koyama E, Young B, Nagayama M, Shibukawa Y, Enomoto-Iwamoto M, Iwamoto M, et al. Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis. Development. 2007;134:2159–69.CrossRefPubMedPubMedCentral

90.

Mundy C, Bello A, Sgariglia F, Koyama E, Pacifici M. HhAntag, a hedgehog signaling antagonist, suppresses chondrogenesis and modulates canonical and non-canonical BMP signaling. J Cell Physiol. 2016;231:1033–44.CrossRefPubMed

Titel: Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments
verfasst von: Maurizio Pacifici
Publikationsdatum: 02.05.2017
Verlag: Springer US
Erschienen in: Current Osteoporosis Reports / Ausgabe 3/2017
Print ISSN: 1544-1873
Elektronische ISSN: 1544-2241
DOI: https://doi.org/10.1007/s11914-017-0355-2

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