Perlecan is a large heparan sulfate proteoglycan that is typically found in basal lamina of adult and embryonic tissues. Recent studies have demonstrated that perlecan accumulates impressively during cartilage development and is maintained as the major heparan sulfate proteoglycan of adult cartilage. In vertebrates, perlecan mutations result in skeletal defects. Moreover, in vitro studies indicate that perlecan can stimulate early stages of cartilage differentiation and cooperate with chondrogenic growth factors to promote this process. This short article will summarize these results and propose a model for perlecan function that incorporates these genetic and cell biological findings.

1.
Aberfeld, D.C., L.P. Hinterbuchner, M. Schneider (1965) Myotonia, dwarfism, diffuse bone disease and unusual ocular and facial abnormalities (a new syndrome). Brain 88: 313–322.
2.
Ahn, J., H.J. Ludecke, S. Lindow, W.A. Horton, B. Lee, M.J. Wagner, B. Horsthemke, D.E. Wells (1995) Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet 11: 137–143.
3.
Arikawa-Hirasawa, E., A.H. Le, I. Nishino, I. Nonaka, N.C. Ho, C.A. Francomano, P. Govindraj, J.R. Hassell, J.M. Devaney, J. Spranger, R.E. Stevenson, S. Iannaccone, M.C. Dalakas, Y. Yamada (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.
4.
Arikawa-Hirasawa, E., H. Watanabe, H. Takami, J.R. Hassell, Y. Yamada (1999) Perlecan is essential for cartilage and cephalic development. Nat Genet 23: 354–358.
5.
Arikawa-Hirasawa, E., W.R. Wilcox, A.H. Le, N. Silverman, P. Govindraj, J.R. Hassell, Y. Yamada (2001a) Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nat Genet 27: 431–434.
6.
Arikawa-Hirasawa, E., W.R. Wilcox, Y. Yamada (2001b) Dyssegmental dysplasia, Silverman-Handmaker type: Unexpected role of perlecan in cartilage development. Am J Med Genet 106: 254–257.
7.
Aviezer, D., D. Hecht, M. Safran, M. Eisinger, G. David, A. Yayon, (1994) Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis. Cell 79: 1005–1013.
8.
Aviezer, D., R.V. Iozzo, D.M. Noonan, A. Yayon (1997) Suppression of autocrine and paracrine functions of basic fibroblast growth factor by stable expression of perlecan antisense cDNA. Mol Cell Biol 17: 1938–1946.
9.
Battaglia, C., M. Aumailley, K. Mann, U. Mayer, R. Timpl (1993) Structural basis of beta 1 integrin-mediated cell adhesion to a large heparan sulfate proteoglycan from basement membranes. Eur J Cell Biol 61: 92–99.
10.
Battaglia, C., U. Mayer, M. Aumailley, R. Timpl (1992) Basement-membrane heparan sulfate proteoglycan binds to laminin by its heparan sulfate chains and to nidogen by sites in the protein core. Eur J Biochem 208: 359–366.
11.
Brown, J.C., T. Sasaki, W. Gohring, Y. Yamada, R. Timpl (1997) The C-terminal domain V of perlecan promotes beta1 integrin-mediated cell adhesion, binds heparin, nidogen and fibulin-2 and can be modified by glycosaminoglycans. Eur J Biochem 250: 39–46.
12.
Chakravarti, S., T. Horchar, B. Jefferson, G.W. Laurie, J.R. Hassell (1995) Recombinant domain III of perlecan promotes cell attachment through its RGDS sequence. J Biol Chem 270: 404–409.
13.
Chakravarti, S., S.L. Phillips, J.R. Hassell (1991) Assignment of the perlecan (heparan sulfate proteoglycan) gene to mouse chromosome 4. Mamm Genome 1: 270–272.
14.
Cohen, I.R., S. Grassel, A.D. Murdoch, R.V. Iozzo, (1993) Structural characterization of the complete human perlecan gene and its promoter. Proc Natl Acad Sci USA 90: 10404–10408.
15.
Costell, M., E. Gustafsson, A. Aszodi, M. Morgelin, W. Bloch, E. Hunziker, K. Addicks, R. Timpl, R. Fassler, (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147: 1109–1122.
16.
Costell, M., T. Sasaki, K. Mann, Y. Yamada, R. Timpl (1996) Structural characterization of recombinant domain II of the basement membrane proteoglycan perlecan. FEBS Lett 396: 127–131.
17.
Couchman, J.R., A.V. Ljubimov (1989) Mammalian tissue distribution of a large heparan sulfate proteoglycan detected by monoclonal antibodies. Matrix 9: 311–321.
18.
Couchman, J.R., A.V. Ljubimov, M. Sthanam, T. Horchar, J.R. Hassell (1995) Antibody mapping and tissue localization of globular and cysteine-rich regions of perlecan domain III. J Histochem Cytochem 43: 955–963.
19.
Datta, S., D.R. Kankel (1992) l(1)trol and l(1)devl, loci affecting the development of the adult central nervous system in Drosophila melanogaster. Genetics 130: 523–537.
20.
Dodge, G.R., E.W. Boesler, S.A. Jimenez (1995) Expression of the basement membrane heparan sulfate proteoglycan (perlecan) in human synovium and in cultured human synovial cells. Lab Invest 73: 649–657.
21.
Dodge, G.R., I. Kovalszky, M.L. Chu, J.R. Hassell, O.W. McBride, H.F. Yi, R.V.Iozzo (1991) Heparan sulfate proteoglycan of human colon: partial molecular cloning, cellular expression, and mapping of the gene (HSPG2) to the short arm of human chromosome 1. Genomics 10: 673–680.
22.
Duncan, G., C. McCormick, F. Tufaro (2001) The link between heparan sulfate and hereditary bone disease: finding a function for the EXT family of putative tumor suppressor proteins. J Clin Invest 108: 511–516.
23.
Durr, J., S. Goodman, A. Potocnik, H. von der Mark, K. von der Mark (1993) Localization of beta 1-integrins in human cartilage and their role in chondrocyte adhesion to collagen and fibronectin. Exp Cell Res 207: 235–244.
24.
Dziadek, M., S. Fujiwara, M. Paulsson, R. Timpl (1985) Immunological characterization of basement membrane types of heparan sulfate proteoglycan. Embo J 4: 905–912.
25.
French, M.M., R.R. Gomes, Jr., R. Timpl, M. Hook, K. Czymmek, M.C. Farach-Carson, D.D. Carson (2002) Chondrogenic activity of the heparan sulfate proteoglycan perlecan maps to the N-terminal domain I. J Bone Miner Res 17: 48–55.
26.
French, M.M., S.E. Smith, K. Akanbi, T. Sanford, J. Hecht, M.C. Farach-Carson, D.D. Carson (1999) Expression of the heparan sulfate proteoglycan, perlecan, during mouse embryogenesis and perlecan chondrogenic activity in vitro. J Cell Biol 145: 1103–1115.
27.
Friedrich, M.V., W. Gohring, M. Morgelin, A. Brancaccio, G. David, R. Timpl (1999) Structural basis of glycosaminoglycan modification and of heterotypic interactions of perlecan domain V. J Mol Biol 294: 259–270.
28.
Gohring, W., T. Sasaki, C.H. Heldin, R. Timpl (1998) Mapping of the binding of platelet-derived growth factor to distinct domains of the basement membrane proteins BM-40 and perlecan and distinction from the BM-40 collagen-binding epitope. Eur J Biochem 255: 60–66.
29.
Gomes, R.R., M.C. Farach-Carson, D.D. Carson (2003) Perlecan-stimulated nodules undergo chondrogenic maturation in response to rhBMP-2 treatment in vitro. Connect Tissue Res 44: 1–6.
30.
Govindraj, P., L. West, T.J. Koob, P. Neame, K. Doege, J.R. Hassell (2002) Isolation and identification of the major heparan sulfate proteoglycans in the developing bovine rib growth plate. J Biol Chem 277: 19461–19469.
31.
Handler, M., P.D. Yurchenco, R.V. Iozzo (1997) Developmental expression of perlecan during murine embryogenesis. Dev Dyn 210: 130–145.
32.
Hassell, J.R., P.G. Robey, H.J. Barrach, J. Wilczek, S.I. Rennard, G.R. Martin (1980) Isolation of a heparan sulfate-containing proteoglycan from basement membrane. Proc Natl Acad Sci USA 77: 4494–4498.
33.
Hayashi, K., J.A. Madri, P.D. Yurchenco (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.
34.
Hecht, J.T., C.R. Hall, M. Snuggs, E. Hayes, R. Haynes, W.G. Cole (2002) Heparan sulfate abnormalities in exostosis growth plates. Bone 31: 199–204.
35.
Heremans, A., J.J. Cassiman, H. Van den Berghe, G. David (1988) Heparan sulfate proteoglycan from the extracellular matrix of human lung fibroblasts. Isolation, purification, and core protein characterization. J Biol Chem 263: 4731–4739.
36.
Hirsch, M.S., L.E. Lunsford, V. Trinkaus-Randall, K.K. Svoboda (1997) Chondrocyte survival and differentiation in situ are integrin mediated. Dev Dyn 210: 249–263.
37.
Hirsch, M.S., K.K. Svoboda (1996) Beta 1 integrin antibodies inhibit chondrocyte terminal differentiation in whole sterna. Ann NY Acad Sci 785: 267–270.
38.
Hopf, M., W. Gohring, K. Mann, R. Timpl (2001) Mapping of binding sites for nidogens, fibulin-2, fibronectin and heparin to different IG modules of perlecan. J Mol Biol 311: 529–541.
39.
Iozzo, R.V., I.R. Cohen, S. Grassel, A.D. Murdoch (1994) The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J 302:(Pt 3): 625–639.
40.
Iozzo, R.V., J. Pillarisetti, B. Sharma, A.D. Murdoch, K.G. Danielson, J. Uitto, A. Mauviel (1997) Structural and functional characterization of the human perlecan gene promoter. Transcriptional activation by transforming growth factor-beta via a nuclear factor 1-binding element. J Biol Chem 272: 5219–5228.
41.
Kanwar, Y.S., M.G. Farquhar (1979) Isolation of glycosaminoglycans (heparan sulfate) from glomerular basement membranes. Proc Natl Acad Sci USA 76: 4493–4497.
42.
Kato, M., Y. Koike, S. Suzuki, K. Kimata (1988) Basement membrane proteoglycan in various tissues: characterization using monoclonal antibodies to the Engelbreth-Holm-Swarm mouse tumor low density heparan sulfate proteoglycan. J Cell Biol 106: 2203–2210.
43.
Klein, G., S. Conzelmann, S. Beck, R. Timpl, C.A. Muller (1995) Perlecan in human bone marrow: a growth-factor-presenting, but anti-adhesive, extracellular matrix component for hematopoietic cells. Matrix Biol 14: 457–465.
44.
Melrose, J., S. Smith, S. Knox, J. Whitelock (2002) Perlecan, the multidomain HS-proteoglycan of basement membranes, is a prominent pericellular component of ovine hypertrophic vertebral growth plate and cartilaginous endplate chondrocytes. Histochem Cell Biol 118: 269–280.
45.
Murdoch, A.D., G.R. Dodge, I. Cohen, R.S. Tuan, R.V. Iozzo (1992) Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J Biol Chem 267: 8544–8557.
46.
Murdoch, A.D., B. Liu, R. Schwarting, R.S. Tuan, R.V. Iozzo (1994) Widespread 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 hybridization. J Histochem Cytochem 42: 239–249.
47.
Noonan, D.M., A. Fulle, P. Valente, S. Cai, E. Horigan, M. Sasaki, Y. Yamada, J.R. Hassell (1991) The complete sequence of perlecan, a basement membrane heparan sulfate proteoglycan, reveals extensive similarity with laminin A chain, low density lipoprotein-receptor, and the neural cell adhesion molecule. J Biol Chem 266: 22939–22947.
48.
Ornitz, D.M., P.J. Marie (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16: 1446–1465.
49.
Rivas, R., F. Shapiro (2002) Structural stages in the development of the long bones and epiphyses: A study in the New Zealand white rabbit. J Bone Joint Surg Am 84-A: 85–100.
50.
Rogalski, T.M., E.J. Gilchrist, G.P. Mullen, D.G. Moerman (1995) Mutations in the unc-52 gene responsible for body wall muscle defects in adult Caenorhabditis elegans are located in alternatively spliced exons. Genetics 139: 159–169.
51.
Rossi, M., H. Morita, R. Sormunen, S. Airenne, M. Kreivi, L. Wang, N. Fukai, B.R. Olsen, K. Tryggvason, R. Soininen (2003) Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J 22:236–245.
52.
Saksela, O., D. Moscatelli, A. Sommer, D.B. Rifkin (1988) Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J Cell Biol 107: 743–751.
53.
Shakibaei, M. (1998) Inhibition of chondrogenesis by integrin antibody in vitro. Exp Cell Res 240: 95–106.
54.
Sharma, B., R.V. Iozzo (1998) Transcriptional silencing of perlecan gene expression by interferon-gamma. J Biol Chem 273: 4642–4646.
55.
Smith, S.E., M.M. French, J. Julian, B.C. Paria, S.K., Dey, D.D. Carson (1997) Expression of heparan sulfate proteoglycan (perlecan) in the mouse blastocyst is regulated during normal and delayed implantation. Dev Biol 184: 38–47.
56.
Stickens, D., G. Clines, D. Burbee, P. Ramos, S. Thomas, D. Hogue, J.T. Hecht, M. Lovett, G.A. Evans (1996) The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet 14: 25–32.
57.
SundarRaj, N., D. Fite, S. Ledbetter, S. Chakravarti, J.R. Hassell (1995) Perlecan is a component of cartilage matrix and promotes chondrocyte attachment. J Cell Sci 108: 2663–2672.
58.
Talts, J.F., Z. Andac, W. Gohring, A. Brancaccio, R. Timpl (1999) Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellular matrix proteins. Embo J 18: 863–870.
59.
Tapanadechopone, P., J.R. Hassell, B. Rigatti, J.R. Couchman (1999) Localization of glycosaminoglycan substitution sites on domain V of mouse perlecan. Biochem Biophys Res Commun 265: X680–690.
60.
van den Born, J., L.P. van den Heuvel, M.A. Bakker, J.H. Veerkamp, K.J. Assmann, J.H. Berden (1994) Monoclonal antibodies against the protein core and glycosaminoglycan side chain of glomerular basement membrane heparan sulfate proteoglycan: characterization and immunohistological application in human tissues. J Histochem Cytochem 42: 89–102.
61.
Vigny, M., M.P. Ollier-Hartmann, M. Lavigne, N. Fayein, J.C. Jeanny, M. Laurent, Y. Courtois (1988) Specific binding of basic fibroblast growth factor to basement membrane-like structures and to purified heparan sulfate proteoglycan of the EHS tumor. J Cell Physiol 137: 321–328.
62.
Wintle, R.F., R. Kisilevsky, D. Noonan, A.M. Duncan (1990) In situ hybridization to human chromosome 1 of a cDNA probe for the gene encoding the basement membrane heparan sulfate proteoglycan (HSPG). Cytogenet Cell Genet 54: 60–61.
63.
Woods, V.L., Jr., P.J. Schreck, D.S. Gesink, H.O. Pacheco, D. Amiel, W.H. Akeson, M. Lotz (1994) Integrin expression by human articular chondrocytes. Arthritis Rheum 37: 537–544.
64.
Wu, J.E., S.A. Santoro (1994) Complex patterns of expression suggest extensive roles for the alpha 2 beta 1 integrin in murine development. Dev Dyn 199: 292–314.
65.
Yayon, A., M. Klagsbrun, J.D. Esko, P. Leder, D.M. Ornitz (1991) Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64: 841–848.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.