Advertisement

Mouse Models in Tendon and Ligament Research

  • Michael J. Mienaltowski
  • David E. BirkEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 802)

Abstract

Mutant mouse models are valuable resources for the study of tendon and ligament biology. Many mutant mouse models are used because their manifested phenotypes mimic clinical pathobiology for several heritable disorders, such as Ehlers-Danlos Syndrome and Osteogenesis Imperfecta. Moreover, these models are helpful for discerning roles of specific genes in the development, maturation, and repair of musculoskeletal tissues. There are several categories of genes with essential roles in the synthesis and maintenance of tendon and ligament structures. The form and function of these tissues depend highly upon fibril-forming collagens, the primary extracellular macromolecules of tendons and ligaments. Models for these fibril-forming collagens, as well as for regulatory molecules like FACITs and SLRPs, are important for studying fibril assembly, growth, and maturation. Additionally, mouse models for growth factors and transcription factors are useful for defining regulation of cell proliferation, cell differentiation, and cues that stimulate matrix synthesis. Models for membrane-bound proteins assess the roles of cell-cell communication and cell-matrix interaction. In some cases, special considerations need to be given to spatio-temporal control of a gene in a model. Thus, conditional and inducible mouse models allow for specific regulation of genes of interest. Advances in mouse models have provided valuable tools for gaining insight into the form and function of tendons and ligaments.

Keywords

Fibril-forming collagens oim mouse model cho mouse model Chondrodysplasia Ppib Crtap or Lepre null mice Col14a1−/− mouse model Collagen XIV Mouse model for mutated Col12a1 Scleraxis transgenic model mice Scx-null (Scx−/−) mice Osteogenesis Imperfecta Haploinsufficient Col3a1+/− and Col5a1+/− mice 

References

  1. 1.
    Birk DE, Mayne R (1997) Localization of collagen types I, III and V during tendon development. Changes in collagen types I and III are correlated with changes in fibril diameter. Eur J Cell Biol 72(4):352–361PubMedGoogle Scholar
  2. 2.
    Riechert K, Labs K, Lindenhayn K, Sinha P (2001) Semiquantitative analysis of types I and III collagen from tendons and ligaments in a rabbit model. J Orthop Sci 6(1):68–74PubMedGoogle Scholar
  3. 3.
    Fukuta S, Oyama M, Kavalkovich K, Fu FH, Niyibizi C (1998) Identification of types II, IX and X collagens at the insertion site of the bovine Achilles tendon. Matrix Biol 17(1):65–73PubMedGoogle Scholar
  4. 4.
    Milz S, Jakob J, Buttner A, Tischer T, Putz R, Benjamin M (2008) The structure of the coracoacromial ligament: fibrocartilage differentiation does not necessarily mean pathology. Scand J Med Sci Sports 18(1):16–22PubMedGoogle Scholar
  5. 5.
    Barker DD, Wu H, Hartung S, Breindl M, Jaenisch R (1991) Retrovirus-induced insertional mutagenesis: mechanism of collagen mutation in Mov13 mice. Mol Cell Biol 11(10):5154–5163PubMedCentralPubMedGoogle Scholar
  6. 6.
    Hartung S, Jaenisch R, Breindl M (1986) Retrovirus insertion inactivates mouse alpha 1(I) collagen gene by blocking initiation of transcription. Nature 320(6060):365–367PubMedGoogle Scholar
  7. 7.
    Jaenisch R, Harbers K, Schnieke A, Lohler J, Chumakov I, Jahner D, Grotkopp D, Hoffmann E (1983) Germline integration of moloney murine leukemia virus at the Mov13 locus leads to recessive lethal mutation and early embryonic death. Cell 32(1):209–216PubMedGoogle Scholar
  8. 8.
    Chipman SD, Sweet HO, McBride DJ Jr, Davisson MT, Marks SC Jr, Shuldiner AR, Wenstrup RJ, Rowe DW, Shapiro JR (1993) Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta. Proc Natl Acad Sci U S A 90(5):1701–1705PubMedCentralPubMedGoogle Scholar
  9. 9.
    Aszodi A, Chan D, Hunziker E, Bateman JF, Fassler R (1998) Collagen II is essential for the removal of the notochord and the formation of intervertebral discs. J Cell Biol 143(5):1399–1412PubMedGoogle Scholar
  10. 10.
    Aszodi A, Hunziker EB, Olsen BR, Fassler R (2001) The role of collagen II and cartilage fibril-associated molecules in skeletal development. Osteoarthr Cartilage 9(Suppl A):S150–S159Google Scholar
  11. 11.
    Rani PU, Stringa E, Dharmavaram R, Chatterjee D, Tuan RS, Khillan JS (1999) Restoration of normal bone development by human homologue of collagen type II (COL2A1) gene in Col2a1 null mice. Dev Dyn 214(1):26–33PubMedGoogle Scholar
  12. 12.
    Cooper TK, Zhong Q, Krawczyk M, Tae HJ, Muller GA, Schubert R, Myers LA, Dietz HC, Talan MI, Briest W (2010) The haploinsufficient Col3a1 mouse as a model for vascular Ehlers-Danlos syndrome. Vet Pathol 47(6):1028–1039PubMedCentralPubMedGoogle Scholar
  13. 13.
    Liu X, Wu H, Byrne M, Krane S, Jaenisch R (1997) Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A 94(5):1852–1856PubMedCentralPubMedGoogle Scholar
  14. 14.
    Smith LB, Hadoke PW, Dyer E, Denvir MA, Brownstein D, Miller E, Nelson N, Wells S, Cheeseman M, Greenfield A (2011) Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome. Cardiovasc Res 90(1):182–190PubMedGoogle Scholar
  15. 15.
    Andrikopoulos K, Liu X, Keene DR, Jaenisch R, Ramirez F (1995) Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assembly. Nat Genet 9(1):31–36PubMedGoogle Scholar
  16. 16.
    Lincoln J, Florer JB, Deutsch GH, Wenstrup RJ, Yutzey KE (2006) ColVa1 and ColXIa1 are required for myocardial morphogenesis and heart valve development. Dev Dyn 235(12):3295–3305PubMedGoogle Scholar
  17. 17.
    Wenstrup RJ, Florer JB, Brunskill EW, Bell SM, Chervoneva I, Birk DE (2004) Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem 279(51):53331–53337PubMedGoogle Scholar
  18. 18.
    Wenstrup RJ, Smith SM, Florer JB, Zhang G, Beason DP, Seegmiller RE, Soslowsky LJ, Birk DE (2011) Regulation of collagen fibril nucleation and initial fibril assembly involves coordinate interactions with collagens V and XI in developing tendon. J Biol Chem 286(23):20455–20465PubMedGoogle Scholar
  19. 19.
    Li Y, Lacerda DA, Warman ML, Beier DR, Yoshioka H, Ninomiya Y, Oxford JT, Morris NP, Andrikopoulos K, Ramirez F et al (1995) A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell 80(3):423–430PubMedGoogle Scholar
  20. 20.
    Byers PH, Bonadio JF, Cohn DH, Starman BJ, Wenstrup RJ, Willing MC (1988) Osteogenesis imperfecta: the molecular basis of clinical heterogeneity. Ann N Y Acad Sci 543:117–128PubMedGoogle Scholar
  21. 21.
    Rohrbach M, Giunta C (2012) Recessive osteogenesis imperfecta: clinical, radiological, and molecular findings. Am J Med Genet C Semin Med Genet 160C(3):175–189PubMedGoogle Scholar
  22. 22.
    Gentry BA, Ferreira JA, McCambridge AJ, Brown M, Phillips CL (2010) Skeletal muscle weakness in osteogenesis imperfecta mice. Matrix Biol 29(7):638–644PubMedCentralPubMedGoogle Scholar
  23. 23.
    McBride DJ Jr, Choe V, Shapiro JR, Brodsky B (1997) Altered collagen structure in mouse tail tendon lacking the alpha 2(I) chain. J Mol Biol 270(2):275–284PubMedGoogle Scholar
  24. 24.
    Misof K, Landis WJ, Klaushofer K, Fratzl P (1997) Collagen from the osteogenesis imperfecta mouse model (oim) shows reduced resistance against tensile stress. J Clin Invest 100(1):40–45PubMedCentralPubMedGoogle Scholar
  25. 25.
    Pfeiffer BJ, Franklin CL, Hsieh FH, Bank RA, Phillips CL (2005) Alpha 2(I) collagen deficient oim mice have altered biomechanical integrity, collagen content, and collagen crosslinking of their thoracic aorta. Matrix Biol 24(7):451–458PubMedGoogle Scholar
  26. 26.
    Bonod-Bidaud C, Roulet M, Hansen U, Elsheikh A, Malbouyres M, Ricard-Blum S, Faye C, Vaganay E, Rousselle P, Ruggiero F (2012) In vivo evidence for a bridging role of a collagen V subtype at the epidermis-dermis interface. J Invest Dermatol 132(7):1841–1849PubMedGoogle Scholar
  27. 27.
    Imamura Y, Scott IC, Greenspan DS (2000) The pro-alpha3(V) collagen chain. Complete primary structure, expression domains in adult and developing tissues, and comparison to the structures and expression domains of the other types V and XI procollagen chains. J Biol Chem 275(12):8749–8759PubMedGoogle Scholar
  28. 28.
    Malfait F, Wenstrup RJ, De Paepe A (2010) Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med 12(10):597–605PubMedGoogle Scholar
  29. 29.
    Symoens S, Syx D, Malfait F, Callewaert B, De Backer J, Vanakker O, Coucke P, De Paepe A (2012) Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum Mutat 33(10):1485–1493PubMedGoogle Scholar
  30. 30.
    Wenstrup RJ, Florer JB, Cole WG, Willing MC, Birk DE (2004) Reduced type I collagen utilization: a pathogenic mechanism in COL5A1 haplo-insufficient Ehlers-Danlos syndrome. J Cell Biochem 92(1):113–124PubMedGoogle Scholar
  31. 31.
    Sun M, Chen S, Adams SM, Florer JB, Liu H, Kao WW, Wenstrup RJ, Birk DE (2011) Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specific Col5a1-null mouse model. J Cell Sci 124(Pt 23):4096–4105PubMedGoogle Scholar
  32. 32.
    Seegmiller R, Fraser FC, Sheldon H (1971) A new chondrodystrophic mutant in mice. Electron microscopy of normal and abnormal chondrogenesis. J Cell Biol 48(3):580–593PubMedGoogle Scholar
  33. 33.
    Tompson SW, Bacino CA, Safina NP, Bober MB, Proud VK, Funari T, Wangler MF, Nevarez L, Ala-Kokko L, Wilcox WR, Eyre DR, Krakow D, Cohn DH (2010) Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene. Am J Hum Genet 87(5):708–712PubMedCentralPubMedGoogle Scholar
  34. 34.
    Rodriguez RR, Seegmiller RE, Stark MR, Bridgewater LC (2004) A type XI collagen mutation leads to increased degradation of type II collagen in articular cartilage. Osteoarthr Cartilage 12(4):314–320Google Scholar
  35. 35.
    Gorres KL, Raines RT (2010) Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol 45(2):106–124PubMedCentralPubMedGoogle Scholar
  36. 36.
    Bruckner P, Eikenberry EF, Prockop DJ (1981) Formation of the triple helix of type I procollagen in cellulo. A kinetic model based on cis-trans isomerization of peptide bonds. Eur J Biochem 118(3):607–613PubMedGoogle Scholar
  37. 37.
    Marini JC, Cabral WA, Barnes AM (2010) Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta. Cell Tissue Res 339(1):59–70PubMedCentralPubMedGoogle Scholar
  38. 38.
    Steinmann B, Bruckner P, Superti-Furga A (1991) Cyclosporin A slows collagen triple-helix formation in vivo: indirect evidence for a physiologic role of peptidyl-prolyl cis-trans-isomerase. J Biol Chem 266(2):1299–1303PubMedGoogle Scholar
  39. 39.
    Baldridge D, Lennington J, Weis M, Homan EP, Jiang MM, Munivez E, Keene DR, Hogue WR, Pyott S, Byers PH, Krakow D, Cohn DH, Eyre DR, Lee B, Morello R (2010) Generalized connective tissue disease in Crtap−/− mouse. PLoS One 5(5):e10560PubMedCentralPubMedGoogle Scholar
  40. 40.
    Chang W, Barnes AM, Cabral WA, Bodurtha JN, Marini JC (2010) Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex. Hum Mol Genet 19(2):223–234PubMedGoogle Scholar
  41. 41.
    Choi JW, Sutor SL, Lindquist L, Evans GL, Madden BJ, Bergen HR 3rd, Hefferan TE, Yaszemski MJ, Bram RJ (2009) Severe osteogenesis imperfecta in cyclophilin B-deficient mice. PLoS Genet 5(12):e1000750PubMedCentralPubMedGoogle Scholar
  42. 42.
    Holster T, Pakkanen O, Soininen R, Sormunen R, Nokelainen M, Kivirikko KI, Myllyharju J (2007) Loss of assembly of the main basement membrane collagen, type IV, but not fibril-forming collagens and embryonic death in collagen prolyl 4-hydroxylase I null mice. J Biol Chem 282(4):2512–2519PubMedGoogle Scholar
  43. 43.
    Vranka J, Stadler HS, Bachinger HP (2009) Expression of prolyl 3-hydroxylase genes in embryonic and adult mouse tissues. Cell Struct Funct 34(2):97–104PubMedGoogle Scholar
  44. 44.
    Vranka JA, Pokidysheva E, Hayashi L, Zientek K, Mizuno K, Ishikawa Y, Maddox K, Tufa S, Keene DR, Klein R, Bachinger HP (2010) Prolyl 3-hydroxylase 1 null mice display abnormalities in fibrillar collagen-rich tissues such as tendons, skin, and bones. J Biol Chem 285(22):17253–17262PubMedGoogle Scholar
  45. 45.
    Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, HP B, Pace JM, Schwarze U, Byers PH, Weis M, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, Lee B (2006) CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 127(2):291–304PubMedGoogle Scholar
  46. 46.
    Ansorge HL, Meng X, Zhang G, Veit G, Sun M, Klement JF, Beason DP, Soslowsky LJ, Koch M, Birk DE (2009) Type XIV collagen regulates fibrillogenesis: premature collagen fibril growth and tissue dysfunction in null mice. J Biol Chem 284(13):8427–8438PubMedGoogle Scholar
  47. 47.
    Izu Y, Sun M, Zwolanek D, Veit G, Williams V, Cha B, Jepsen KJ, Koch M, Birk DE (2011) Type XII collagen regulates osteoblast polarity and communication during bone formation. J Cell Biol 193(6):1115–1130PubMedGoogle Scholar
  48. 48.
    Koch M, Bernasconi C, Chiquet M (1992) A major oligomeric fibroblast proteoglycan identified as a novel large form of type-XII collagen. Eur J Biochem 207(3):847–856PubMedGoogle Scholar
  49. 49.
    Niyibizi C, Visconti CS, Kavalkovich K, Woo SL (1995) Collagens in an adult bovine medial collateral ligament: immunofluorescence localization by confocal microscopy reveals that type XIV collagen predominates at the ligament-bone junction. Matrix Biol 14(9):743–751PubMedGoogle Scholar
  50. 50.
    Zhang G, Young BB, Birk DE (2003) Differential expression of type XII collagen in developing chicken metatarsal tendons. J Anat 202(5):411–420PubMedGoogle Scholar
  51. 51.
    Fluck M, Giraud M, Tunc V, Chiquet M (2003) Tensile stress-dependent collagen XII and fibronectin production by fibroblasts requires separate pathways. Biochim Biophys Acta 1593(2–3):239–248PubMedGoogle Scholar
  52. 52.
    Nishiyama T, McDonough AM, Bruns RR, Burgeson RE (1994) Type XII and XIV collagens mediate interactions between banded collagen fibers in vitro and may modulate extracellular matrix deformability. J Biol Chem 269(45):28193–28199PubMedGoogle Scholar
  53. 53.
    Jin X, Iwasa S, Okada K, Ooi A, Mitsui K, Mitsumata M (2003) Shear stress-induced collagen XII expression is associated with atherogenesis. Biochem Biophys Res Commun 308(1):152–158PubMedGoogle Scholar
  54. 54.
    Arai K, Nagashima Y, Takemoto T, Nishiyama T (2008) Mechanical strain increases expression of type XII collagen in murine osteoblastic MC3T3-E1 cells. Cell Struct Funct 33(2):203–210PubMedGoogle Scholar
  55. 55.
    Chiquet M, Mumenthaler U, Wittwer M, Jin W, Koch M (1998) The chick and human collagen alpha1(XII) gene promoter – activity of highly conserved regions around the first exon and in the first intron. Eur J Biochem 257(2):362–371PubMedGoogle Scholar
  56. 56.
    Reichenberger E, Baur S, Sukotjo C, Olsen BR, Karimbux NY, Nishimura I (2000) Collagen XII mutation disrupts matrix structure of periodontal ligament and skin. J Dent Res 79(12):1962–1968PubMedGoogle Scholar
  57. 57.
    Ameye L, Young MF (2002) Mice deficient in small leucine-rich proteoglycans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases. Glycobiology 12(9):107R–116RPubMedGoogle Scholar
  58. 58.
    Chakravarti S (2002) Functions of lumican and fibromodulin: lessons from knockout mice. Glycoconj J 19(4–5):287–293PubMedGoogle Scholar
  59. 59.
    Chen S, Birk DE (2013) The regulatory roles of small leucine-rich proteoglycans in extracellular matrix assembly. FEBS J 280(10):2120–2137. PMC#3651807PubMedGoogle Scholar
  60. 60.
    Kalamajski S, Oldberg A (2010) The role of small leucine-rich proteoglycans in collagen fibrillogenesis. Matrix Biol 29(4):248–253PubMedGoogle Scholar
  61. 61.
    Ezura Y, Chakravarti S, Oldberg A, Chervoneva I, Birk DE (2000) Differential expression of lumican and fibromodulin regulate collagen fibrillogenesis in developing mouse tendons. J Cell Biol 151(4):779–788PubMedGoogle Scholar
  62. 62.
    Zhang G, Young BB, Ezura Y, Favata M, Soslowsky LJ, Chakravarti S, Birk DE (2005) Development of tendon structure and function: regulation of collagen fibrillogenesis. J Musculoskelet Neuronal Interact 5(1):5–21PubMedGoogle Scholar
  63. 63.
    Jepsen KJ, Wu F, Peragallo JH, Paul J, Roberts L, Ezura Y, Oldberg A, Birk DE, Chakravarti S (2002) A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. J Biol Chem 277(38):35532–35540PubMedGoogle Scholar
  64. 64.
    Ameye L, Aria D, Jepsen K, Oldberg A, Xu T, Young MF (2002) Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis. FASEB J 16(7):673–680PubMedGoogle Scholar
  65. 65.
    Dunkman AA, Buckley MR, Mienaltowski MJ, Adams SM, Thomas SJ, Satchell L, Kumar A, Pathmanathan L, Beason DP, Iozzo RV, Birk DE, Soslowsky LJ (2013) Decorin expression is important for age-related changes in tendon structure and mechanical properties. Matrix Biol 32(1):3–13. PMC#3615887PubMedCentralPubMedGoogle Scholar
  66. 66.
    Zhang G, Ezura Y, Chervoneva I, Robinson PS, Beason DP, Carine ET, Soslowsky LJ, Iozzo RV, Birk DE (2006) Decorin regulates assembly of collagen fibrils and acquisition of biomechanical properties during tendon development. J Cell Biochem 98(6):1436–1449PubMedGoogle Scholar
  67. 67.
    Svensson L, Heinegard D, Oldberg A (1995) Decorin-binding sites for collagen type I are mainly located in leucine-rich repeats 4–5. J Biol Chem 270(35):20712–20716PubMedGoogle Scholar
  68. 68.
    Zhang G, Chen S, Goldoni S, Calder BW, Simpson HC, Owens RT, McQuillan DJ, Young MF, Iozzo RV, Birk DE (2009) Genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by decorin and biglycan. J Biol Chem 284(13):8888–8897PubMedGoogle Scholar
  69. 69.
    Ansorge HL, Adams S, Birk DE, Soslowsky LJ (2011) Mechanical, compositional, and structural properties of the post-natal mouse Achilles tendon. Ann Biomed Eng 39(7):1904–1913PubMedCentralPubMedGoogle Scholar
  70. 70.
    Young MF, Bi Y, Ameye L, Chen XD (2002) Biglycan knockout mice: new models for musculoskeletal diseases. Glycoconj J 19(4–5):257–262PubMedGoogle Scholar
  71. 71.
    Kilts T, Ameye L, Syed-Picard F, Ono M, Berendsen AD, Oldberg A, Heegaard AM, Bi Y, Young MF (2009) Potential roles for the small leucine-rich proteoglycans biglycan (Bgn) and fibromodulin (Fmod) in ectopic ossification of tendon induced by exercise and in rotarod performance. Scand J Med Sci Sports 19(4):536–546PubMedCentralPubMedGoogle Scholar
  72. 72.
    Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF (2007) Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 13(10):1219–1227PubMedGoogle Scholar
  73. 73.
    Wadhwa S, Embree MC, Kilts T, Young MF, Ameye LG (2005) Accelerated osteoarthritis in the temporomandibular joint of biglycan/fibromodulin double-deficient mice. Osteoarthr Cartilage 13(9):817–827Google Scholar
  74. 74.
    Mienaltowski MJ, Adams SM, Birk DE (2013) Regional differences in stem cell/progenitor cell populations from the mouse Achilles tendon. Tissue Eng Part A 19(1–2):199–210. PMC#3530943PubMedGoogle Scholar
  75. 75.
    Svensson L, Aszodi A, Reinholt FP, Fassler R, Heinegard D, Oldberg A (1999) Fibromodulin-null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendon. J Biol Chem 274(14):9636–9647PubMedGoogle Scholar
  76. 76.
    Bruns RR, Press W, Engvall E, Timpl R, Gross J (1986) Type VI collagen in extracellular, 100-nm periodic filaments and fibrils: identification by immunoelectron microscopy. J Cell Biol 103(2):393–404PubMedGoogle Scholar
  77. 77.
    Furthmayr H, Wiedemann H, Timpl R, Odermatt E, Engel J (1983) Electron-microscopical approach to a structural model of intima collagen. Biochem J 211(2):303–311PubMedGoogle Scholar
  78. 78.
    von der Mark H, Aumailley M, Wick G, Fleischmajer R, Timpl R (1984) Immunochemistry, genuine size and tissue localization of collagen VI. Eur J Biochem 142(3):493–502PubMedGoogle Scholar
  79. 79.
    Kielty C, Grant ME (2002) The collagen family: structure, assembly, and organization in the extracellular matrix. In: Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders. Wiley-Liss, New York, pp 159–222Google Scholar
  80. 80.
    Lampe AK, Bushby KM (2005) Collagen VI related muscle disorders. J Med Genet 42(9):673–685PubMedGoogle Scholar
  81. 81.
    Bonaldo P, Braghetta P, Zanetti M, Piccolo S, Volpin D, Bressan GM (1998) Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet 7(13):2135–2140PubMedGoogle Scholar
  82. 82.
    Christensen SE, Coles JM, Zelenski NA, Furman BD, Leddy HA, Zauscher S, Bonaldo P, Guilak F (2012) Altered trabecular bone structure and delayed cartilage degeneration in the knees of collagen VI null mice. PLoS One 7(3):e33379Google Scholar
  83. 83.
    Izu Y, Ansorge HL, Zhang G, Soslowsky LJ, Bonaldo P, Chu ML, Birk DE (2011) Dysfunctional tendon collagen fibrillogenesis in collagen VI null mice. Matrix Biol 30(1):53–61PubMedCentralPubMedGoogle Scholar
  84. 84.
    Izu Y, Ezura Y, Mizoguchi F, Kawamata A, Nakamoto T, Nakashima K, Hayata T, Hemmi H, Bonaldo P, Noda M (2012) Type VI collagen deficiency induces osteopenia with distortion of osteoblastic cell morphology. Tissue Cell 44(1):1–6PubMedGoogle Scholar
  85. 85.
    Arteaga-Solis E, Sui-Arteaga L, Kim M, Schaffler MB, Jepsen KJ, Pleshko N, Ramirez F (2011) Material and mechanical properties of bones deficient for fibrillin-1 or fibrillin-2 microfibrils. Matrix Biol 30(3):188–194PubMedCentralPubMedGoogle Scholar
  86. 86.
    Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, Stetten G, Meyers DA, Francomano CA (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352(6333):337–339PubMedGoogle Scholar
  87. 87.
    Lee B, Godfrey M, Vitale E, Hori H, Mattei MG, Sarfarazi M, Tsipouras P, Ramirez F, Hollister DW (1991) Linkage of Marfan syndrome and a phenotypically related disorder to different fibrillin genes. Nature 352(6333):330–334PubMedGoogle Scholar
  88. 88.
    Ritty TM, Ditsios K, Starcher BC (2002) Distribution of the elastic fiber and associated proteins in flexor tendons reflects function. Anat Rec 268(4):430–440PubMedGoogle Scholar
  89. 89.
    Smith KD, Vaughan-Thomas A, Spiller DG, Innes JF, Clegg PD, Comerford EJ (2011) The organisation of elastin and fibrillins 1 and 2 in the cruciate ligament complex. J Anat 218(6):600–607PubMedGoogle Scholar
  90. 90.
    Boregowda R, Paul E, White J, Ritty TM (2008) Bone and soft connective tissue alterations results from loss of fibrillin-2 expression. Matrix Biol 27(8):661–666PubMedGoogle Scholar
  91. 91.
    Nistala H, Lee-Arteaga S, Smaldone S, Siciliano G, Carta L, Ono RN, Sengle G, Arteaga-Solis E, Levasseur R, Ducy P, Sakai LY, Karsenty G, Ramirez F (2010) Fibrillin-1 and −2 differentially modulate endogenous TGF-beta and BMP bioavailability during bone formation. J Cell Biol 190(6):1107–1121PubMedGoogle Scholar
  92. 92.
    Miller G, Neilan M, Chia R, Gheryani N, Holt N, Charbit A, Wells S, Tucci V, Lalanne Z, Denny P, Fisher EM, Cheeseman M, Askew GN, Dear TN (2010) ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2. PLoS One 5(2):e9137PubMedCentralPubMedGoogle Scholar
  93. 93.
    Cook JR, Smaldone S, Cozzolino C, Del Solar M, Lee-Arteaga S, Nistala H, Ramirez F (2012) Generation of Fbn1 conditional null mice implicates the extracellular microfibrils in osteoprogenitor recruitment. Genesis 50(8):635–641PubMedCentralPubMedGoogle Scholar
  94. 94.
    Mendias CL, Bakhurin KI, Faulkner JA (2008) Tendons of myostatin-deficient mice are small, brittle, and hypocellular. Proc Natl Acad Sci U S A 105(1):388–393PubMedCentralPubMedGoogle Scholar
  95. 95.
    Edom-Vovard F, Bonnin MA, Duprez D (2001) Misexpresison of Fgf-4 in the chick limb inhibits myogenesis by down-regulating Frek expression. Dev Biol 233(1):56–71PubMedGoogle Scholar
  96. 96.
    Edom-Vovard F, Schuler B, Bonnin MA, Teillet MA, Duprez D (2002) Fgf4 positively regulates scleraxis and tenascin expression in chick limb tendons. Dev Biol 247(2):351–366PubMedGoogle Scholar
  97. 97.
    Edom-Vovard F, Bonnin MA, Duprez D (2001) Fgf8 transcripts are located in tendons during embryonic chick limb development. Mech Dev 108(1–2):203–206PubMedGoogle Scholar
  98. 98.
    Galatz L, Rothermich S, VanderPloeg K, Petersen B, Sandell L, Thomopoulos S (2007) Development of the supraspinatus tendon-to-bone insertion: localized expression of extracellular matrix and growth factor genes. J Orthop Res 25(12):1621–1628PubMedGoogle Scholar
  99. 99.
    Kuo CK, Peterson BC, Tuan RS (2008) Spatiotemporal protein distribution of TGF-Bs, their receptor, and extracellular matrix molecules during embryonic tendon development. Dev Dyn 237(5):1477–1489PubMedCentralPubMedGoogle Scholar
  100. 100.
    Schweitzer R, Chyung JH, Murtaugh LC, Brent AE, Rosen V, Olson EN, Lassar A, Tabin CJ (2001) Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 128(19):3855–3866PubMedGoogle Scholar
  101. 101.
    Kobayashi M, Minagawa H, Miyakoshi N, Takahashi S, Tuoheti Y, Okada K, Shimada Y (2006) Expression of growth factors in the early phase of supraspinatus tendon healing in rabbits. J Should Elbow Surg 15(3):371–377Google Scholar
  102. 102.
    Galatz L, Sandell LJ, Rothermich SY, Das R, Mastny A, Havlioglu N, Silva MJ, Thomopoulos S (2006) Characteristics of the rat supraspinatus tendon during tendon-to-bone healing after acute injury. J Orthop Res 24(3):541–550PubMedGoogle Scholar
  103. 103.
    Hirose K, Kondo S, Choi HR, Mishima S, Iwata H, Ishiguro N (2004) Spontaneous healing process of a supraspinatus tear in rabbits. Arch Orthop Trauma Surg 124(6):374–377PubMedGoogle Scholar
  104. 104.
    Dines JS, Grande DA, Dines DM (2007) Tissue engineering and rotator cuff tendon healing. J Should Elbow Surg 16(5 Suppl):S204–S207Google Scholar
  105. 105.
    Wϋrgler CC, Dourte LM, Baradet TC, Williams GR, Soslowsky LJ (2007) Temporal expression of 8 growth factors in tendon-to-bone healing in a rat supraspinatus model. J Should Elbow Surg 16(5 Suppl):S198–S203Google Scholar
  106. 106.
    Crowe MJ, Doetschman T, Greenhalgh DG (2000) Delayed wound healing in immunodeficient TGF-beta 1 knockout mice. J Invest Dermatol 115(1):3–11PubMedGoogle Scholar
  107. 107.
    Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T (1997) Tgfbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124(13):2659–2670PubMedCentralPubMedGoogle Scholar
  108. 108.
    Pryce BA, Watson SS, Murchison ND, Staverosky JA, Dunker N, Schweitzer R (2009) Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation. Development 136(8):1351–1361PubMedGoogle Scholar
  109. 109.
    Dunker N, Krieglstein K (2002) Tgfbeta2 −/− Tgfbeta3 −/− double knockout mice display severe midline fusion defects and early embryonic lethality. Anat Embryol (Berl) 206(1–2):73–83Google Scholar
  110. 110.
    Dunker N, Schmitt K, Krieglstein K (2002) TGF-beta is required for programmed cell death in interdigital webs of the developing mouse limb. Mech Dev 113(2):111–120PubMedGoogle Scholar
  111. 111.
    Tsubone T, Moran SL, Subramaniam M, Amadio PC, Spelsberg TC, An KN (2006) Effect of TGF-beta inducible early gene deficiency on flexor tendon healing. J Orthop Res 24(3):569–575PubMedGoogle Scholar
  112. 112.
    Mikic B (2004) Multiple effects of GDF-5 deficiency on skeletal tissues: implications for therapeutic bioengineering. Ann Biomed Eng 32(3):466–476PubMedGoogle Scholar
  113. 113.
    Storm EE, Huynh TV, Copeland NG, Jenkins NA, Kingsley DM, Lee S-J (1994) Limb alteration in brachypodism mice due to mutations in a new member of the TGF-beta superfamily. Nature 368(6472):639–643PubMedGoogle Scholar
  114. 114.
    Duke J, Elmer WA (1977) Effect of the brachypod mutation on cell adhesion and chondrogenesis in aggregates of mouse limb mesenchyme. J Embryol Exp Morphol 42:209–217Google Scholar
  115. 115.
    Mikic B, Battaglia TC, Taylor EA, Clark RT (2002) The effect of growth/differentiation factor-5 deficiency on femoral composition and mechanical behavior in mice. Bone 30(5):733–737PubMedGoogle Scholar
  116. 116.
    Daans M, Luyten FP, Lories RJ (2011) GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes. Ann Rheum Dis 70(1):208–213PubMedGoogle Scholar
  117. 117.
    Mikic B, Schalet BJ, Clark RT, Gaschen V, Hunziker E (2001) GDF-5 deficiency in mice alters the ultrastructure, mechanical properties and composition of the Achilles tendon. J Orthop Res 19(3):365–371PubMedGoogle Scholar
  118. 118.
    Chhabra A, Tsou D, Clark RT, Gaschen V, Hunziker EB, Mikic B (2003) GDF-5 deficiency in mice delays Achilles tendon healing. J Orthop Res 21(5):826–835PubMedGoogle Scholar
  119. 119.
    Mikic B, Rossmeier K, Bierwert L (2009) Identification of a tendon phenotype in GDF6 deficient mice. Anat Rec (Hoboken) 292(3):396–400Google Scholar
  120. 120.
    Mikic B, Rossmeier K, Bierwert L (2009) Sexual dimorphism in the effect of GDF-6 deficiency on murine tendon. J Orthop Res 27(12):1603–1611PubMedCentralPubMedGoogle Scholar
  121. 121.
    Mikic B, Bierwert L, Tsou D (2006) Achilles tendon characterization in GDF-7 deficient mice. J Orthop Res 24(4):831–841PubMedGoogle Scholar
  122. 122.
    Mikic B, Entwistle R, Rossmeier K, Bierwert L (2008) Effect of GDF-7 deficiency on tail tendon phenotype in mice. J Orthop Res 26(6):834–839PubMedGoogle Scholar
  123. 123.
    Asou Y, Nifuji A, Tsuji K, Shinomiya K, Olson EN, Koopman P, Noda M (2002) Coordinated expression of scleraxis and Sox9 genes during embryonic development of tendons and cartilage. J Orthop Res 20(4):827–833PubMedGoogle Scholar
  124. 124.
    Cserjesi P, Brown D, Ligon KL, Lyons GE, Copeland NG, Gilbert DJ, Jenkins NA, Olson EN (1995) Scleraxis: a basic helix-loop-helix protein that prefigures skeletal formation during mouse embryogenesis. Development 121(4):1099–1110PubMedGoogle Scholar
  125. 125.
    Perez AV, Perrine M, Brainard N, Vogel KG (2003) Scleraxis (Scx) directs lacZ expression in tendon of transgenic mice. Mech Dev 120(10):1153–1163PubMedGoogle Scholar
  126. 126.
    Brent AE, Tabin CJ (2004) FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression. Development 131(16):3885–3896PubMedGoogle Scholar
  127. 127.
    Shukunami C, Takimoto A, Oro M, Hiraki Y (2006) Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev Biol 298(1):234–247PubMedGoogle Scholar
  128. 128.
    Scott A, Sampaio A, Abraham T, Duronio C, Underhill TM (2011) Scleraxis expression is coordinately regulated in a murine model of patellar tendon injury. J Orthop Res 29(2):289–296PubMedGoogle Scholar
  129. 129.
    Alberton P, Popov C, Pragert M, Kohler J, Shukunami C, Schieker M, Docheva D (2012) Conversion of human bone marrow-derived mesenchymal stem cells into tendon progenitor cells by ectopic expression of scleraxis. Stem Cells Dev 21(6):846–858PubMedGoogle Scholar
  130. 130.
    Pryce BA, Brent AE, Murchison ND, Tabin CJ, Schweitzer R (2007) Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene. Dev Dyn 236(6):1677–1682PubMedGoogle Scholar
  131. 131.
    Mendias CL, Gumucio JP, Bakhurin KI, Lynch EB, Brooks SV (2012) Physiological loading of tendons induces scleraxis expression in epitenon fibroblasts. J Orthop Res 30(4):606–612PubMedCentralPubMedGoogle Scholar
  132. 132.
    Wang L, Bresee CS, Jiang H, He W, Ren T, Schweitzer R, Brigande JV (2011) Scleraxis is required for differentiation of the stapedius and tensor tympani tendons of the middle ear. J Assoc Res Otolaryngol 12(4):407–421PubMedCentralPubMedGoogle Scholar
  133. 133.
    Murchison ND, Price BA, Conner DA, Keene DR, Olson EN, Tabin CJ, Schweitzer R (2007) Regulation of tendon differentiation by scleraxis distinguishes force-transmitting tendons from muscle-anchoring tendons. Development 134(14):2697–2708PubMedGoogle Scholar
  134. 134.
    Ito Y, Toriuchi N, Yoshitaka T, Ueno-Kudoh H, Sato T, Yokoyama S, Nishida K, Akimoto T, Takahashi M, Miyaki S, Asahara H (2010) The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc Natl Acad Sci U S A 107(23):10538–10542PubMedCentralPubMedGoogle Scholar
  135. 135.
    Liu W, Watson SS, Lan Y, Keene DR, Ovitt CE, Liu H, Schweitzer R, Jiang R (2010) The atypical homeodomain transcription factor Mohawk controls tendon morphogenesis. Mol Cell Biol 30(20):4797–4807PubMedCentralPubMedGoogle Scholar
  136. 136.
    Becker S, Pasca G, Strumpf D, Min L, Volk T (1997) Reciprocal signaling between Drosophila epidermal muscle attachment cells and their corresponding muscles. Development 124(13):2615–2622PubMedGoogle Scholar
  137. 137.
    Frommer G, Vorbruggen G, Pasca G, Jacke H, Volk T (1996) Epidermal egr-like zinc finger protein of Drosophila participates in myotube guidance. EMBO J 15(7):1642–1649PubMedGoogle Scholar
  138. 138.
    Lejard V, Blais F, Guerquin MJ, Bonnet A, Bonnin MA, Havis E, Malbouyres M, Bidaud CB, Maro G, Gilardi-Hebenstreit P, Rossert J, Ruggiero F, Duprez D (2011) EGR1 and EGR2 involvement in vertebrate tendon differentiation. J Biol Chem 286(7):5855–5867PubMedGoogle Scholar
  139. 139.
    Shukunami C, Oshima Y, Hiraki Y (2005) Chondromodulin-I and tenomodulin: a new class of tissue-specific angiogenesis inhibitors found in hypovascular connective tissues. Biochem Biophys Res Commun 333(2):299–307PubMedGoogle Scholar
  140. 140.
    Docheva D, Hunziker EB, Fassler R, Brandau O (2005) Tenomodulin is necessary for tenocyte proliferation and tendon maturation. Mol Cell Biol 25(2):699–705PubMedCentralPubMedGoogle Scholar
  141. 141.
    Pure E, Cuff CA (2001) A crucial role for CD44 in inflammation. Trends Mol Med 7(5):213–221PubMedGoogle Scholar
  142. 142.
    Carter WG, Wayner EA (1988) Characterization of the class III collagen receptor, a phosphorylated, transmembrane glycoprotein expressed in nucleated human cells. J Biol Chem 263(9):4193–4201PubMedGoogle Scholar
  143. 143.
    Yagi M, Sato N, Mitsui Y, Gotoh M, Hamada T, Nagata K (2010) Hyaluronan modulates proliferation and migration of rabbit fibroblasts derived from flexor tendon epitenon and endotenon. J Hand Surg [Am] 35(5):791–796Google Scholar
  144. 144.
    Ansorge HL, Beredjiklian PK, Soslowsky LJ (2009) CD44 deficiency improves healing tendon mechanics and increases matrix and cytokine expression in a mouse patellar tendon injury model. J Orthop Res 27(10):1386–1391PubMedCentralPubMedGoogle Scholar
  145. 145.
    Chen S, Sun M, Meng X, Iozzo RV, Kao WW, Birk DE (2011) Pathophysiological mechanisms of autosomal dominant congenital stromal corneal dystrophy: C-terminal-truncated decorin results in abnormal matrix assembly and altered expression of small leucine-rich proteoglycans. Am J Pathol 179(5):2409–2419PubMedGoogle Scholar
  146. 146.
    Valjent E, Bertran-Gonzalez J, Herve D, Fisone G, Girault JA (2009) Looking BAC at striatal signaling: cell-specific analysis in new transgenic mice. Trends Neurosci 32(10):538–547PubMedGoogle Scholar
  147. 147.
    Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ (2002) Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33(2):77–80PubMedGoogle Scholar
  148. 148.
    Seo HS, Serra R (2007) Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev Biol 310(2):304–316PubMedCentralPubMedGoogle Scholar
  149. 149.
    Rinkevich Y, Lindau P, Ueno H, Longaker MT, Weissman IL (2011) Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip. Nature 476(7361):409–413PubMedGoogle Scholar
  150. 150.
    Soeda T, Deng JM, de Crombrugghe B, Behringer RR, Nakamura T, Akiyama H (2010) Sox9-expressing precursors are the cellular origin of the cruciate ligament of the knee joint and the limb tendons. Genesis 48(11):635–644PubMedGoogle Scholar
  151. 151.
    Zha L, Hou N, Wang J, Yang G, Gao Y, Chen L, Yang X (2008) Collagen1alpha1 promoter drives the expression of Cre recombinase in osteoblasts of transgenic mice. J Genet Genomics 35(9):525–530PubMedGoogle Scholar
  152. 152.
    Zhu M, Chen M, Lichtler AC, O'Keefe RJ, Chen D (2008) Tamoxifen-inducible Cre-recombination in articular chondrocytes of adult Col2a1-CreER(T2) transgenic mice. Osteoarthr Cartil 16(1):129–130PubMedCentralPubMedGoogle Scholar
  153. 153.
    Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Lubbert H, Bujard H (1996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A 93(20):10933–10938PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Departments of Molecular Pharmacology & Physiology and Orthopaedics & Sports MedicineUniversity of South Florida, Morsani College of MedicineTampaUSA

Personalised recommendations