Skip to main content
SpringerLink
Log in

Tgfbi Deficiency Leads to a Reduction in Skeletal Size and Degradation of the Bone Matrix

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Transforming growth factor-β-induced gene product-h3 (TGFBI/BIGH3) is an extracellular matrix protein expressed in a wide variety of tissues. TGFBI binds to type I, II, and IV collagens, as well as to biglycan and decorin and plays important roles in cell-to-cell, cell-to-collagen, and cell-to-matrix interactions. Furthermore, TGFBI is involved in cell growth and migration, tumorigenesis, wound healing, and apoptosis. To investigate whether TGFBI is involved in the maintenance of skeletal tissues, Tgfbi knockout mice were generated by crossing male and female Tgfbi heterozygous mice. Skeletal preparation showed that the skeletal size in Tgfbi knockout mice was smaller than in wild-type and heterozygous mice. However, chondrocytic cell alignment in the growth plates, bone mineral density, and bone forming rates were similar in Tgfbi knockout, wild-type, and heterozygous mice. Alterations in skeletal tissue arrangements in Tgfbi knockout mice were estimated from safranin O staining, trichrome staining, and immunohistochemistry for type II and X collagen, and matrix metalloproteinase 13 (MMP13). Cartilage matrix degradation was observed in the articular cartilage of Tgfbi knockout mice. Although the detection of type II collagen in the articular cartilage was lower in Tgfbi knockout mice than wild-type mice, the detection of MMP13 was markedly higher, indicating that Tgfbi deficiency is associated with the degradation of cartilage matrix. These results suggest that TGFBI plays an important role in maintaining skeletal tissues and the cartilage matrix in mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Skonier J, Neubauer M, Madisen L, Bennett K, Plowman GD, Purchio AF (1992) cDNA cloning and sequence analysis of betaig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-beta. DNA Cell Biol 11:511–522

    Article  CAS  PubMed  Google Scholar 

  2. Kawamoto T, Noshiro M, Shen M, Nakamasu K, Hashimoto K, Kawashima-Ohya Y, Gotoh O, Kato Y (1998) Structural and phylogenetic analyses of RGD-CAP/beta ig-h3, a fasciclin-like adhesion protein expressed in chick chondrocytes. Biochim Biophys Acta 1395:288–292

    Article  CAS  PubMed  Google Scholar 

  3. Skonier J, Benenett K, Rothwell V, Kosowski S, Plowman G, Wallace P, Edelhoff S, Disteche C, Neubauer M, Marquardt H, Rodgers J, Purchio AF (1994) beta ig-h3: a transforming growth factor-beta-responsive gene encoding a secreted protein that inhibits cell attachment in vitro and suppresses the growth of CHO cells in nude mice. DNA Cell Biol 13:571–584

    Article  CAS  PubMed  Google Scholar 

  4. Ma C, Rong Y, Radiloff DR, Datto MB, Centeno B, Bao S, Cheng AW, Lin F, Jiang S, Yeatman TJ, Wang XF (2008) Extracellular matrix protein beta ig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation. Genes Dev 22:308–321

    Article  PubMed Central  PubMed  Google Scholar 

  5. Rawe IM, Zhan Q, Burrows R, Bennett K, Cintron C (1997) Beta-ig. Molecular cloning and in situ hybridization in corneal tissues. Invest Ophthalmol Vis Sci 38:893–900

    CAS  PubMed  Google Scholar 

  6. Kim JE, Kim SJ, Jeong HW, Lee BH, Choi JY, Park RW, Park JY, Kim IS (2003) RGD peptides released from beta ig-h3, a TGF-beta-induced cell-adhesive molecule, mediate apoptosis. Oncogene 22:2045–2053

    Article  CAS  PubMed  Google Scholar 

  7. LeBaron RG, Bezverkov KI, Zimber MP, Pavele R, Skonier J, Purchio AF (1995) Beta IGH3, a novel secretory protein inducible by transforming growth factor-beta, is present in normal skin and promotes the adhesion and spreading of dermal fibroblasts in vitro. J Invest Dermatol 104:844–849

    Article  CAS  PubMed  Google Scholar 

  8. Ohno S, Noshiro M, Makihira S, Kawamoto T, Shen M, Yan W, Kawashima-Ohya Y, Fujimoto K, Tanne K, Kato Y (1999) RGD-CAP ((beta)ig-h3) enhances the spreading of chondrocytes and fibroblasts via integrin alpha(1)beta(1). Biochim Biophys Acta 1451:196–205

    Article  CAS  PubMed  Google Scholar 

  9. Kim JE, Kim SJ, Lee BH, Park RW, Kim KS, Kim IS (2000) Identification of motifs for cell adhesion within the repeated domains of transforming growth factor-β-induced gene, βig-h3. J Biol Chem 275:30907–30915

    Article  CAS  PubMed  Google Scholar 

  10. Schorderet DF, Menasche M, Morand S, Bonnel S, Buchillier V, Marchant D, Auderset K, Bonny C, Abitbol M, Munier FL (2000) Genomic characterization and embryonic expression of the mouse Bigh3 (Tgfbi) gene. Biochem Biophys Res Commun 274:267–274

    Article  CAS  PubMed  Google Scholar 

  11. Han MS, Kim JE, Shin HI, Kim IS (2008) Expression patterns of βig-h3 in chondrocyte differentiation during endochondral ossification. Exp Mol Med 40:453–460

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Thorp BH, Anderson I, Jakowlew SB (1992) Transforming growth factor-beta 1, -beta 2 and -beta 3 in cartilage and bone cells during endochondral ossification in the chick. Development 114:907–911

    CAS  PubMed  Google Scholar 

  13. Blaney Davidson EN, van der Kraan PM, van den Berg WB (2007) TGF-beta and osteoarthritis. Osteoarthr Cartil 15:597–604

    Article  CAS  PubMed  Google Scholar 

  14. Yang X, Chen L, Xu X, Li C, Huang C, Deng CX (2001) TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 153:35–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Tang SY, Alliston T (2013) Regulation of postnatal bone homeostasis by TGF-β. Bonekey Rep 255:1–5

    Google Scholar 

  16. Kim JE, Park RW, Choi JY, Bae YC, Kim KS, Joo CK, Kim IS (2002) Molecular properties of wild-type and mutant βIG-H3 proteins. Invest Ophthalmol Vis Sci 43:656–661

    PubMed  Google Scholar 

  17. Bae JS, Lee W, Nam JO, Kim JE, Kim SW, Kim IS (2014) Transforming growth factor-β-induced protein promotes severe vascular inflammatory responses. Am J Resp Crit Care 189:779–786

    Article  Google Scholar 

  18. Baek WY, Lee MA, Jung JW, Kim SY, Akiyama H, de Crombrugghe B, Kim JE (2009) Positive regulation of adult bone formation by osteoblast-specific transcription factor Osterix. J Bone Miner Res 24:1055–1065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Baek WY, de Crombrugghe B, Kim JE (2010) Postnatally induced inactivation of Osterix in osteoblasts results in the reduction of bone formation and maintenance. Bone 46:920–928

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Erben RG (1997) Embedding of bone samples in methylmethacrylate: an improved method suitable for bone histomorphometry, histochemistry, and immunohistochemistry. J Histochem Cytochem 45:307–313

    Article  CAS  PubMed  Google Scholar 

  21. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610

    Article  CAS  PubMed  Google Scholar 

  22. Bancroft JD, Layton C (2012) Connective and mesenchymal tissue with their stains. In: Suvarna SK, Layton C, Bancroft JD (eds) Bancroft’s theory and practice of histological techniques. Churchill Livingstone Elsevier, Oxford, pp 187–214

    Google Scholar 

  23. Yu H, Yang X, Cheng J, Wang X, Shen SG (2011) Distraction osteogenesis combined with tissue-engineered cartilage in the reconstruction of condylar osteochondral defect. J Oral Maxillofac Surg 69:e558–e564

    Article  PubMed  Google Scholar 

  24. Shimizu S, Asou Y, Itoh S, Chung UI, Kawaguchi H, Shinomiya K, Muneta T (2007) Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis. Arthritis Rheum 56:3358–3365

    Article  PubMed  Google Scholar 

  25. Estrada LE, Dodge GR, Richardson DW, Farole A, Jimenez SA (2001) Characterization of a biomaterial with cartilage-like properties expressing type X collagen generated in vitro using neonatal porcine articular and growth plate chondrocytes. Osteoarthr Cartil 9:169–177

    Article  CAS  PubMed  Google Scholar 

  26. Mankin HJ, Dorfman H, Lippiello L, Zarins A (1971) Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am 53:523–537

    CAS  PubMed  Google Scholar 

  27. Aigner T, Cook JL, Gerwin N, Glasson SS, Laverty S, Little CB, McIlwraith W, Kraus VB (2010) Histopathology atlas of animal model systems—overview of guiding principles. Osteoarthr Cartil 18(Suppl 3):S2–S6

    Article  PubMed  Google Scholar 

  28. Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T, Uchida M, Ogata N, Seichi A, Nakamura K, Kawaguchi H (2005) Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthr Cartil 13:632–641

    Article  CAS  PubMed  Google Scholar 

  29. Chen B, Qin J, Wang H, Magdalou J, Chen L (2010) Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits. Exp Mol Med 42:684–695

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Eyre DR, Weis MA, Wu JJ (2006) Articular cartilage collagen: an irreplaceable framework? Eur Cell Mater 12:57–63

    CAS  PubMed  Google Scholar 

  31. Roberts AB, Mccune BK, Sporn MB (1992) TGF-β: regulation of extracellular matrix. Kidney Int 41:557–559

    Article  CAS  PubMed  Google Scholar 

  32. Wong M, Carter DR (2003) Articular cartilage functional histomorphology and mechanobiology: a research perspective. Bone 33:1–13

    Article  CAS  PubMed  Google Scholar 

  33. Munger JS, Sheppard D (2011) Cross talk among TGF-β signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb Perspect Biol 3:a005017

    Article  PubMed Central  PubMed  Google Scholar 

  34. Varga J, Jimenez SA (1986) Stimulation of normal human fibroblast collagen production and processing by transforming growth factor-beta. Biochem Biophys Res Commun 138:974–980

    Article  CAS  PubMed  Google Scholar 

  35. Ruiz-Ortega M, Rodríguez-Vita J, Sanchez-Lopez E, Carvajal G, Egido J (2007) TGF-β signaling in vascular fibrosis. Cardiovasc Res 74:196–206

    Article  CAS  PubMed  Google Scholar 

  36. Allen JL, Cooke ME, Alliston T (2012) ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation. Mol Biol Cell 23:3731–3742

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Thapa N, Lee BH, Kim IS (2007) TGFBIp/betaig-h3 protein: a versatile matrix molecule induced by TGF-beta. Int J Biochem Cell Biol 39:2183–2194

    Article  CAS  PubMed  Google Scholar 

  38. Munier FL, Korvatska E, Djemai A, Le Paslier D, Zografos L, Pescia G, Schorderet DF (1997) Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 15:247–251

    Article  CAS  PubMed  Google Scholar 

  39. Kim JE, Han MS, Bae YC, Kim HK, Kim TI, Kim EK, Kim IS (2007) Anterior segment dysgenesis after overexpression of transforming growth factor-beta-induced gene, beta igh3, in the mouse eye. Mol Vis 13:1942–1952

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Billings PC, Whitbeck JC, Adams CS, Abrams WR, Cohen AJ, Engelsberg BN, Howard PS, Rosenbloom J (2002) The transforming growth factor-beta-inducible matrix protein (beta)ig-h3 interacts with fibronectin. J Biol Chem 277:28003–28009

    Article  CAS  PubMed  Google Scholar 

  41. Hanssen E, Reinboth B, Gibson MA (2003) Covalent and non-covalent interactions of betaig-h3 with collagen VI. Beta ig-h3 is covalently attached to the amino-terminal region of collagen VI in tissue microfibrils. J Biol Chem 278:24334–24341

    Article  CAS  PubMed  Google Scholar 

  42. Reinboth B, Thomas J, Hanssen E, Gibson MA (2006) Beta ig-h3 interacts directly with biglycan and decorin, promotes collagen VI aggregation, and participates in ternary complexing with these macromolecules. J Biol Chem 281:7816–7824

    Article  CAS  PubMed  Google Scholar 

  43. Zhang Y, Wen G, Shao G, Wang C, Lin C, Fang H, Balajee AS, Bhagat G, Hei TK, Zhao Y (2009) TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res 69:37–44

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Yu H, Wergedal JE, Zhao Y, Mohan S (2012) Targeted disruption of TGFBI in mice reveals its role in regulating bone mass and bone size through periosteal bone formation. Calcif Tissue Int 91:81–87

    Article  CAS  PubMed  Google Scholar 

  45. McDonnell S, Morgan M, Lynch C (1999) Role of matrix metalloproteinases in normal and disease processes. Biochem Soc Trans 27:734–740

    CAS  PubMed  Google Scholar 

  46. Vincenti MP, Coon CI, Mengshol JA, Yocum S, Mitchell P, Brinckerhoff CE (1998) Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1). Biochem J 331:341–346

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Little C, Barai A, Burkhardt D, Smith S, Fosang A, Werb Z, Shah M, Thompson E (2009) Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 60:3723–3733

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Neuhold LA, Killar L, Zhao W, Sung ML, Warner L, Kulik J, Turner J, Wu W, Billinghurst C, Meijers T, Poole AR, Babij P, DeGennaro LJ (2001) Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 107:35–44

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI13C1874).

Conflict of Interest

Jung-Mi Lee, Eun-Hye Lee, In-San Kim and Jung-Eun Kim state that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All procedures of animal experiments were approved by the Institutional Animal Care and Use Committee of Kyungpook National University.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, Kyungpook National University School of Medicine, Daegu, 700-422, Republic of Korea

    Jung-Mi Lee, Eun-Hye Lee & Jung-Eun Kim

  2. Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, 700-422, Republic of Korea

    In-San Kim

  3. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea

    In-San Kim

  4. Cell and Matrix Research Institute, Kyungpook National University, Daegu, 700-422, Republic of Korea

    Jung-Mi Lee, Eun-Hye Lee, In-San Kim & Jung-Eun Kim

  5. BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, 700-422, Republic of Korea

    Jung-Mi Lee, In-San Kim & Jung-Eun Kim

Authors
  1. Jung-Mi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun-Hye Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. In-San Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jung-Eun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jung-Eun Kim.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, JM., Lee, EH., Kim, IS. et al. Tgfbi Deficiency Leads to a Reduction in Skeletal Size and Degradation of the Bone Matrix. Calcif Tissue Int 96, 56–64 (2015). https://doi.org/10.1007/s00223-014-9938-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-014-9938-4

Keywords

Search

Navigation