Skip to main content

Advertisement

SpringerLink
Log in

Perlecan displays variable spatial and temporal immunolocalisation patterns in the articular and growth plate cartilages of the ovine stifle joint

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Perlecan is a modular heparan sulphate and/or chondroitin sulphate substituted proteoglycan of basement membrane, vascular tissues and cartilage. Perlecan acts as a low affinity co-receptor for fibroblast growth factors 1, 2, 7, 9, binds connective tissue growth factor and co-ordinates chondrogenesis, endochondral ossification and vascular remodelling during skeletal development; however, relatively little is known of its distribution in these tissues during ageing and development. The aim of the present study was to immunolocalise perlecan in the articular and epiphyseal growth plate cartilages of stifle joints in 2-day to 8-year-old pedigree merino sheep. Perlecan was prominent pericellularly in the stifle joint cartilages at all age points and also present in the inter-territorial matrix of the newborn to 19-month-old cartilage specimens. Aggrecan was part pericellular, but predominantly an extracellular proteoglycan. Perlecan was a prominent component of the long bone growth plates and displayed a pericellular as well as a strong ECM distribution pattern; this may indicate a so far unrecognised role for perlecan in the mineralisation of hypertrophic cartilage. A significant age dependant decline in cell number and perlecan levels was evident in the hyaline and growth plate cartilages. The prominent pericellular distribution of perlecan observed indicates potential roles in cell-matrix communication in cartilage, consistent with growth factor signalling, cellular proliferation and tissue development.

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
Fig. 5

Similar content being viewed by others

References

  • Abreu JG, Ketpura NI, Reversade B, De Robertis EM. (2002) Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol 4:599–604

    CAS  PubMed  Google Scholar 

  • Arikawa-Hirasawa E, Watanabe H, Takami H , Hassell JR, Yamada Y (1999) Perlecan is essential for cartilage and cephalic development. Nat Gen 23:354–358

    Article  CAS  Google Scholar 

  • Arikawa-Hirasawa E, Wilcox WR, Yamada Y (2001a) Dyssegmental dysplasia, Silverman-Handmaker type: unexpected role of perlecan in cartilage development. Am J Med Genet 106:254–257

    Article  CAS  PubMed  Google Scholar 

  • Arikawa-Hirasawa E, Wilcox WR, Le AH, Silverman N, Govindraj P, Hassell JR, Yamada Y (2001b) Dyssegmental dyspalsia, Silverman-Handmaker type is caused by functional null mutations of the perlecan gene. Nat Gen 27:431–434

    Article  CAS  Google Scholar 

  • Arikawa-Hirasawa E, Le AH, Nishino I, Nonaka I, Ho NC, Francomano CA, Govindraj P, Hassell JR, Devaney JM, Spranger J, Stevenson RE, Iannaccone S, Dalakas MC, Yamada Y (2002) Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. Am J Hum Genet 70:1368–1375

    Article  CAS  PubMed  Google Scholar 

  • Aviezer D, Hecht D, Safran M, Eisinger M, David G, Yayon A (1994) Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis. Cell 79:1005–1013

    Article  CAS  PubMed  Google Scholar 

  • Bargmann CI (1994) Molecular mechanisms of mechanosensation? Cell 78:729–731

    Article  CAS  PubMed  Google Scholar 

  • Bengtsson E, Mörgelin M, Sasaki T, Timpl R, Heinegard D, Aspberg A (2002) The leucine-rich repeat protein PRELP binds perlecan and collagens and may function as a basement membrane anchor. J Biol Chem 277:15061–15068

    Article  CAS  PubMed  Google Scholar 

  • Bix G, Fu J, Gonzalez EM, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Hook M, Reed CC, Iozzo RV (2004) Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin. J Cell Biol 166:97–109

    Article  CAS  PubMed  Google Scholar 

  • Brown JC, Sasaki T, Göhring W, Yamada Y, Timpl R (1997) The C-terminal domain V of perlecan promotes β1 integrin-mediated cell adhesion, binds heparin, nidogen and fibulin-2 and can be modified by glycosaminoglycans. Eur J Biochem 250:39–46

    Article  CAS  PubMed  Google Scholar 

  • Campbell ID (2003) Modular proteins at the cell surface. Biochem Soc Trans 31:1107–1114

    CAS  PubMed  Google Scholar 

  • Chang Z, Meyer K, Rapraeger AC, Friedl A (2000) Differential ability of HS proteoglycans to assemble the fibroblast growth factor receptor complex in situ. FASEB J 14:137–144

    CAS  PubMed  Google Scholar 

  • Costell M, Mann K, Yamada Y, Timpl R, (1997) Characterization of recombinant perlecan domain I and its substitution by glycosaminoglycans and oligosaccharides. Eur J Biochem 243:115–121

    Article  CAS  PubMed  Google Scholar 

  • Costell M, Gustafsson E, Aszodi A, Morgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fassler R (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147:1109–1122

    Article  CAS  PubMed  Google Scholar 

  • Dolan M, Horchar T, Rigatti B, Hassell JR, (1997) Identification of sites in domain I of perlecan that regulate heparan sulfate synthesis. J Biol Chem 272:4316–4322

    Article  CAS  PubMed  Google Scholar 

  • Ettner N, Gohring W, Sasaki T, Mann K, Timpl R (1998) The N-terminal globular domain of the laminin alpha1 chain binds to alpha1beta1 and alpha 2 beta 1 integrins and to the heparan sulfate-containing domains of perlecan. FEBS Lett 430:217–221

    Article  CAS  PubMed  Google Scholar 

  • French MM, Smith SE, Akanbi K, Sanford T, Hecht J, Farach-Carson MC, Carson DD (1999) Expression of HS proteoglycan, perlecan, during mouse embryogenesis and perlecan chondrogenic activity in-vitro. J Cell Biol 145:1103–1115

    Article  CAS  PubMed  Google Scholar 

  • Friedrich MVK, Göhring W, Mörgelin M, Brancaccio A, David G, Timpl R (1999) Structural basis of GAG modification and of heterotypic interactions of perlecan domain V. J Mol Biol 294:259–270

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Anoveros J, Corey DP (1997) The molecules of mechanosensation. Annu Rev Neurosci 20:567–594

    Article  CAS  PubMed  Google Scholar 

  • Gomes RR, Farach-Carson MC, Carson DD (2004) Perlecan functions in chondrogenesis: insights from in vitro and in vivo models. Cells Tissues Organs 176:79–86

    Article  CAS  PubMed  Google Scholar 

  • Gustafsson E, Aszodi A, Ortega N, Hunziker EB, Denker HW, Werb Z, Fassler R (2003) Role of collagen type II and perlecan in skeletal development. Ann N Y Acad Sci 995:140–150

    CAS  PubMed  Google Scholar 

  • Handler M, Yurchenko PD, Iozzo RV (1997) developmental expression of perlecan during murine embryogenesis. Dev Dyn 210:130–145

    Article  CAS  PubMed  Google Scholar 

  • Hardingham TE (1998) Chapter 5. Cartilage : aggrecan-link protein-hyaluronan aggregates http://www.glycoforum.gr.jp/science/hyaluronan/HA05/HA05E.html

  • Hascall VC, HeinegÃ¥rd D (1974) Aggregation of cartilage proteoglycans. The role of hyaluronic acid. J Biol Chem 249:4232–4241

    CAS  PubMed  Google Scholar 

  • Hassell J, Yamada Y, Arikawa-Hirasawa E (2002) Role of perlecan in skeletal development and diseases. Glycoconj J 19:263–267

    Article  CAS  PubMed  Google Scholar 

  • Hayashi K, Madri JA, Yurchenco PD (1992) Endothelial cells interact with the core protein of basement membrane perlecan through beta 1 and beta 3 integrins: an adhesion modulated by glycosaminoglycan. J Cell Biol 119:945–959

    Article  CAS  PubMed  Google Scholar 

  • Hopf M, Göhring W, Mann K, Timpl R (2001) Mapping of binding sites for nidogens, fibulin-2, fibronectin and heparin to different IG modules of perlecan. J Mol Biol 311:529–541

    Article  CAS  PubMed  Google Scholar 

  • Ingber DE (2003) Mechanosensation through integrins: cells act locally but think globally. Proc Natl Acad Sci USA 100:1472–4

    Article  CAS  PubMed  Google Scholar 

  • Iozzo RV (2001) Heparan sulphate proteoglycans: intricate molecules with intriguing functions. J Clin Invest 108:165–167

    CAS  PubMed  Google Scholar 

  • Iozzo RV, Cohen IR, Grässel S, Murdoch AD (1994) The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J 302:625–639

    CAS  PubMed  Google Scholar 

  • Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130:2779–2791

    Article  CAS  PubMed  Google Scholar 

  • Kallunki P, Tryggvason K (1992) Human basement membrane heparan sulfate proteoglycan core protein: a 467-kD protein containing multiple domains resembling elements of the low density lipoprotein receptor, laminin neural cell adhesion molecules, and epidermal growth factor. J Cell Biol 116:559–571

    Article  CAS  PubMed  Google Scholar 

  • Klint P, Claesson-Welsh L (1999) Signal transduction by fibroblast growth factor receptors. Frontiers Biosci 4:D165–177

    CAS  Google Scholar 

  • Knox S, Melrose J, Whitelock J (2001) Electrophoretic, biosensor and bioactivity analyses of perlecans of different cellular origins. Proteomics 1:1534–1541

    Article  CAS  PubMed  Google Scholar 

  • Knox S, Merry C, Stringer S, Melrose J, Whitelock J (2002) Not all perlecans are created equal: interactions with fibroblast growth factor-2 (FGF-2) and FGF receptors. J Biol Chem 277:14657–14665

    CAS  PubMed  Google Scholar 

  • Kokenyesi R, Silbert JE (1995) Formation of heparan sulfate or chondroitin/dermatan sulfate on recombinant domain I of mouse perlecan expressed in chinese hamster ovary cells. Biochem Biophys Res Commun 211:262–267

    Article  CAS  PubMed  Google Scholar 

  • Legeai-Mallet L, Benoist-Lasselin C, Munnich A, Bonaventure J (2004) Overexpression of FGFR 3, Stat 1, Stat 5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR 3-related chondrodysplasias. Bone 34:26–36

    Article  CAS  PubMed  Google Scholar 

  • Melrose J, Smith S, Knox S, Whitelock J (2002) Perlecan, the multi-domain proteoglycan of basement membrane is also a prominent pericellular component of hypertrophic chondrocytes of ovine vertebral growth plate and cartilaginous end plate cartilage. Histochem Cell Biol 118:269–280

    CAS  PubMed  Google Scholar 

  • Melrose J, Smith S, Ghosh P, Whitelock JW (2003) Perlecan the multi-domain heparan sulphate proteoglycan of Basement membranes is also a prominent component of the cartilaginous primordia in the developing human foetal spine. J Histochem Cytochem 51:1331–1341

    CAS  PubMed  Google Scholar 

  • Melrose J, Susan Smith S, Whitelock J (2004) Perlecan immunolocalises to perichondrial vessels and canals in human foetal cartilaginous primordia in early vascular and matrix remodelling events associated with diarthrodial-joint development. J Histochem Cytochem 52:1405–1413

    Article  CAS  PubMed  Google Scholar 

  • Meyer AN, Gastwirt RF, Schlaepfer DD, Donoghue DJ (2004) The cytoplasmic tyrosine kinase Pyk 2 as a novel effector of fibroblast growth factor receptor 3 activation. J Biol Chem 279:28450–28457

    Article  CAS  PubMed  Google Scholar 

  • Miosge N, Simniok T, Sprysch P, Herken R (2003) The collagen type XVIII endostatin domain is co-localized with perlecan in basement membranes in vivo. J Histochem Cytochem 51:285–296

    CAS  PubMed  Google Scholar 

  • Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown AM, Iozzo RV (2003a) Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J Biol Chem 278:17491–17499

    Article  CAS  PubMed  Google Scholar 

  • Mongiat M, Sweeney SM, San Antonio JD, Fu J, Iozzo R (2003b) Endorepellin, a novel inhibitor of angiogenesis derived from the C-terminus of perlecan. J Biol Chem 278:4238–4249

    Article  CAS  PubMed  Google Scholar 

  • Murdoch AD, Dodge GR, Cohen I, Tuan RS, Iozzo RV (1992) Primary structure of the human heparan sulphate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecule, and epidermal growth factor. J Biol Chem 267:8544–8557

    CAS  PubMed  Google Scholar 

  • Murdoch AD, Liu B, Schwarting R, Tuan RS, Iozzo RV (1994) Wide spread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissues as detected by a novel monoclonal antibody against domain III and by In-situ Hybridisation. J Histochem Cytochem 42:239–249

    CAS  PubMed  Google Scholar 

  • Naski MC, Colvin JS, Coffin JD, Ornitz DM (1998) Repression of hedgehog signalling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125:4977–4988

    CAS  PubMed  Google Scholar 

  • Nicole S, Davoine CS, Topaloglu H, Cattolico L, Barral D, Beighton P, Hamida CB, Hammouda H, Cruaud C, White PS, Samson D, Urtizberea JA, Lehmann-Horn F, Weissenbach J, Hentati F, Fontaine B (2000) Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat Genet 26:480–483

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Kubota S, Fukunaga T, Kondo S, Yosimichi G, Nakanishi T, Takano-Yamamoto T, Takigaw M (2003) CTGF/Hcs24, hypertrophic chondrocyte-specific gene product, interacts with perlecan in regulating the proliferation and differentiation of chondrocytes. J Cell Physiol 196:265–275

    Google Scholar 

  • Noonan DM, Fulle A, Nalente P, Cai S, Horigan E, Sasaki M, Yamada Y, Hassell JR (1991) The complete sequence of perlecan, a basement membrane heparan sulphate proteoglycan reveals extensive similarity with laminin-A chain, low density lipoprotein receptor and the neural cell adhesion molecule. J Biol Chem 266:22939–22947

    CAS  PubMed  Google Scholar 

  • Ornitz DM (2000) FGFs, heparan sulphate and FGFRs: complex interactions essential for development. BioEssays 22:108–112

    Article  CAS  PubMed  Google Scholar 

  • Ornitz DM, Itoh N (2001) Fibroblast growth factors Genome Biology, 2 reviews 3005.1-3005.12. http://genomebiology.com/2001/2/3/reviews/3005

  • Ornitz DM, Leder P (1992) Ligand specificity and heparin dependance of fibroblast growth factor receptors 1 and 3. J Biol Chem 267:16305–16311

    CAS  PubMed  Google Scholar 

  • Sasaki T, Costell M, Mann K, Timpl R (1998) Inhibition of glycosaminoglycan modification of perlecan domain I by site-directed mutagenesis changes protease sensitivity and laminin-1 binding activity. FEBS Lett 435:169–172

    Article  CAS  PubMed  Google Scholar 

  • Schulze B, Sasaki T, Costell M, Mann K, Timpl R (1996) Structural and cell-adhesive properties of three recombinant fragments derived from perlecan domain III. Matrix Biol 15:349–57

    Article  CAS  PubMed  Google Scholar 

  • SundarRaj N, Fite D, Ledbetter S, Chakravarti S, Hassell JR(1995) Perlecan is a component of cartilage matrix and promotes chondrocyte attachment. J Cell Sci 108:2663–2672

    CAS  PubMed  Google Scholar 

  • Sztrolovics R, White RJ, Roughley PJ, Mort JS (2002) The mechanism of aggrecan release from cartilage differs with tissue origin and the agent used to stimulate catabolism. Biochem J 362:465–472

    Article  CAS  PubMed  Google Scholar 

  • Tapanadechopone P, Hassell JR, Rigatti B, Couchman JR (1999) Localization of glycosaminoglycan substitution sites on domain V of mouse perlecan. Biochem Biophys Res Commun 265:680–690

    Article  CAS  PubMed  Google Scholar 

  • Tesche F, Miosge N (2004) Perlecan in late stages of osteoarthritis of the human knee joint. Osteoarthritis Cartilage 12:852–62

    Article  CAS  PubMed  Google Scholar 

  • Tesche F, Miosge N (2005) New aspects of the pathogenesis of osteoarthritis: the role of fibroblast-like chondrocytes in late stages of the disease. Histol Histopathol 20:329–37

    CAS  PubMed  Google Scholar 

  • Tu H, Sasaki T, Snellman A, Göhring W, Pirilä P, Timpl R, Pihlajaniemi T (2002) The type XIII collagen ectodomain is a 150nm rod and capable of binding to fibronectin, nidogen-2, perlecan, and heparin. J Biol Chem 277:23092–23099

    Article  CAS  PubMed  Google Scholar 

  • Wilcox WR, Tavormina PL, Krakow D, Kitoh H, Lachman RS, Wasmuth JJ, Thompson LM, Rimoin Dl (1998) Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet 78:274–281

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Dr. John Mort (Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada) is thanked for his kind gift of a rabbit anti-aggrecan G1 domain polyclonal antibody. This study was supported by the National Health and Medical Research Council (Project Grant No 211266) and by Research Grants from The Arthritis Foundation of Australia and Rebecca-Cooper Medical Research Foundation whose support is greatly appreciated.

Author information

Authors and Affiliations

  1. Raymond Purves Laboratory, Institute of Bone and Joint Research, University of Sydney at the Royal North Shore Hospital, St Leonards, NSW, 2065, Australia

    James Melrose & Susan Smith

  2. School of Veterinary and Biomedical Sciences, Murdoch University, Perth, Australia

    Martin Cake & Richard Read

  3. Graduate School of Biomedical Engineering, University of New South Wales, Kensington, NSW, 2052, Australia

    John Whitelock

  4. Raymond Purves Bone and Joint Research Laboratories, Institute of Bone and Joint Research, Level 5, The University Clinic, The Royal North Shore Hospital, Building B26, St Leonards, NSW, 2065

    James Melrose

Authors
  1. James Melrose
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Cake
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Read
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Whitelock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James Melrose.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Melrose, J., Smith, S., Cake, M. et al. Perlecan displays variable spatial and temporal immunolocalisation patterns in the articular and growth plate cartilages of the ovine stifle joint. Histochem Cell Biol 123, 561–571 (2005). https://doi.org/10.1007/s00418-005-0789-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-005-0789-y

Keywords

Search

Navigation