Current Osteoporosis Reports

, Volume 8, Issue 2, pp 77–83

Role of Cartilage-Associated Protein in Skeletal Development

Article

Abstract

The past 3 years have been exciting for collagen biologists and human geneticists studying the disease known as osteogenesis imperfecta (OI or brittle bone disease). Functional studies on cartilage-associated protein (Crtap) have identified it as an essential component of a heterotrimeric, endoplasmic reticulum resident complex responsible for collagen prolyl 3-hydroxylation and chaperone function. Importantly, human mutations in the CRTAP gene have been associated with recessive forms of OI. Although the function and in vivo biological significance of the 3-hydroxyproline modification are still poorly understood, studies on Crtap have led to the identification of additional genes in which mutations also cause recessive forms of OI. These discoveries have now focused the interest of geneticists on the endoplasmic reticulum that will require the help of biochemists to unravel the molecular dynamics and complexities of collagen folding.

Keywords

Cartilage-associated protein Crtap mutations Skeletal development Osteogenesis imperfecta 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Gehron Robey P, Boskey A: The composition of bone. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Edited by Rosen CJ. Washington, DC: American Society for Bone and Mineral Research; 2008:32–38.CrossRefGoogle Scholar
  2. 2.
    Myllyharju J, Kivirikko KI: Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 2004, 20:33–43.CrossRefPubMedGoogle Scholar
  3. 3.
    Castagnola P, Gennari M, Morello R, et al.: Cartilage associated protein (CASP) is a novel developmentally regulated chick embryo protein. J Cell Sci 1997, 110(Pt 12):1351–1359.PubMedGoogle Scholar
  4. 4.
    Morello R, Tonachini L, Monticone M, et al.: cDNA cloning, characterization and chromosome mapping of Crtap encoding the mouse cartilage associated protein. Matrix Biol 1999, 18:319–324.CrossRefPubMedGoogle Scholar
  5. 5.
    Morello R, Bertin TK, Chen Y, et al.: CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 2006, 127:291–304.CrossRefPubMedGoogle Scholar
  6. 6.
    Morello R, Baldridge D, Lennington J, et al.: Comparative Phenotypic and Biochemical Analyses of Crtap−/− Mice and Patients with Recessive Osteogenesis Imperfecta. [abstract FR0141]. Presented at the ASBMR 31st Annual Meeting. Denver, CO; September 11–15, 2009.Google Scholar
  7. 7.
    Vranka JA, Sakai LY, Bachinger HP: Prolyl 3-hydroxylase 1: enzyme characterization and identification of a novel family of enzymes. J Biol Chem 2004, 279:23615–23621.CrossRefPubMedGoogle Scholar
  8. 8.
    Jarnum S, Kjellman C, Darabi A, et al.: LEPREL1, a novel ER and Golgi resident member of the Leprecan family. Biochem Biophys Res Commun 2004, 317:342–351.CrossRefPubMedGoogle Scholar
  9. 9.
    Rauch F, Glorieux FH: Osteogenesis imperfecta. Lancet 2004, 363:1377–1385.CrossRefPubMedGoogle Scholar
  10. 10.
    Ward LM, Rauch F, Travers R, et al.: Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 2002, 31:12–18.CrossRefPubMedGoogle Scholar
  11. 11.
    Glorieux FH, Rauch F, Plotkin H, et al.: Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000, 15:1650–1658.CrossRefPubMedGoogle Scholar
  12. 12.
    Glorieux FH, Ward LM, Rauch F, et al.: Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2002, 17:30–38.CrossRefPubMedGoogle Scholar
  13. 13.
    Labuda M, Morissette J, Ward LM, et al.: Osteogenesis imperfecta type VII maps to the short arm of chromosome 3. Bone 2002, 31:19–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Barnes AM, Chang W, Morello R, et al.: Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 2006, 355:2757–2764.CrossRefPubMedGoogle Scholar
  15. 15.
    • Baldridge, D., Schwarze U, Morello R, et al.: CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta. Hum Mutat 2008, 29:1435–1442. This article provides clinical and molecular information of patients with recessive OI and expands the phenotype of the disorder.CrossRefPubMedGoogle Scholar
  16. 16.
    Bodian DL, Chan TF, Poon A, et al.: Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships. Hum Mol Genet 2009, 18:463–471.CrossRefPubMedGoogle Scholar
  17. 17.
    • Van Dijk FS, Nesbitt IM, Nikkels PG, et al.: CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis. Eur J Hum Genet 2009, 17:1560–1569. This article describes the phenotype of recessive OI due to CRTAP mutations and discusses the diagnostic work-up in such patients.CrossRefPubMedGoogle Scholar
  18. 18.
    Cheung MS, Glorieux FH, Rauch F: Intravenous pamidronate in osteogenesis imperfecta type VII. Calcif Tissue Int 2009, 84:203–209.CrossRefPubMedGoogle Scholar
  19. 19.
    Baldridge D, Schwarze U, Morello R, et al.: CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta. Hum Mutat 2008, 29:1435–1442.CrossRefPubMedGoogle Scholar
  20. 20.
    Zeitlin L, Rauch F, Plotkin H, Glorieux FH: Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics 2003, 111(5 Pt 1):1030–1036.CrossRefPubMedGoogle Scholar
  21. 21.
    Obafemi AA, Bulas DI, Troendle J, Marini JC: Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation. Am J Med Genet A 2008, 146A:2725–2732.CrossRefPubMedGoogle Scholar
  22. 22.
    Munns CF, Rauch F, Mier RJ, Glorieux FH: Respiratory distress with pamidronate treatment in infants with severe osteogenesis imperfecta. Bone 2004, 35:231–234.CrossRefPubMedGoogle Scholar
  23. 23.
    •• Cabral WA, Chang W, Barnes AM, et al.: Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 2007, 39:359–365. This is the first article describing LEPRE1 mutations in recessive OI patients.CrossRefPubMedGoogle Scholar
  24. 24.
    •• Ishikawa Y, Wirz J, Vranka JA, et al.: Biochemical characterization of the prolyl 3-hydroxylase 1.cartilage-associated protein.cyclophilin B complex. J Biol Chem 2009, 284:17641–17647. This study demonstrates that the prolyl 3-hydroxylation complex, formed by Crtap/P3h1/CypB, also has collagen chaperone activity.CrossRefPubMedGoogle Scholar
  25. 25.
    •• Glorieux FFS, Nesbitt IM, Zwikstra EH, et al.: PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet 2009, 85:521–527. This study demonstrates that mutations in the gene encoding the third component of the prolyl 3-hydroxylation complex, CypB, also cause recessive OI.CrossRefGoogle Scholar
  26. 26.
    • Alanay Y, Avaygan H, Camacho N, et al.: Mutations in a gene encoding a rough endoplasmic reticulum protein causes autosomal recessive progressive deforming osteogenesis imperfecta. [abstract 212]. Presented at the ASHG 59th Annual Meeting. Honolulu, HI; October 20–24, 2009. Identification of FKBP65 mutations, another collagen chaperone molecule, in recessive OI cases negative for mutation in COL1A1, COL1A2, CRTAP, and LEPRE1 demonstrates the importance of collagen chaperone molecules in human disease.Google Scholar
  27. 27.
    • Drogemuller C, Becker D, Brunner A, et al.: A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta. PLoS Genet 2009, 5:e1000579. This article identifies the first mutations in the gene coding HSP47, a collagen-specific chaperone, in a dog strain affected with recessive OI.CrossRefPubMedGoogle Scholar
  28. 28.
    Myllyharju J: Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol 2003, 22:15–24.CrossRefPubMedGoogle Scholar
  29. 29.
    Kefalides NA: Structure and biosynthesis of basement membranes. Int Rev Connect Tissue Res 1973, 6:63–104.PubMedGoogle Scholar
  30. 30.
    Jenkins CL, Bretscher LE, Guzei IA, Raines RT: Effect of 3-hydroxyproline residues on collagen stability. J Am Chem Soc 2003, 125:6422–6427.CrossRefPubMedGoogle Scholar
  31. 31.
    Mizuno K, Peyton DH, Hayashi T, et al.: Effect of the -Gly-3(S)-hydroxyprolyl-4(R)-hydroxyprolyl- tripeptide unit on the stability of collagen model peptides. FEBS J 2008, 275:5830–5840.CrossRefPubMedGoogle Scholar
  32. 32.
    Birk DE, Fitch JM, Babiarz JP, et al.: Collagen fibrillogenesis in vitro: interaction of types I and V collagen regulates fibril diameter. J Cell Sci 1990, 95(Pt 4):649–657.PubMedGoogle Scholar
  33. 33.
    Wenstrup RJ, Florer, JB, Brunskill EW, et al.: Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem 2004, 279:53331–53337.CrossRefPubMedGoogle Scholar
  34. 34.
    Wenstrup RJ, Langland GT, Willing MC, et al.: A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro alpha 1(V) chains results in the gravis form of the Ehlers-Danlos syndrome (type I). Hum Mol Genet 1996, 5:1733–1736.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Physiology and BiophysicsUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Genetics Unit, Shriners Hospital for Children, Department of PediatricsMcGill UniversityMontrealCanada

Personalised recommendations