The Structure, Location, and Function of Perlecan, a Prominent Pericellular Proteoglycan of Fetal, Postnatal, and Mature Hyaline Cartilages

The aim of this study was to immunolocalize perlecan in human fetal, postnatal, and mature hyaline cartilages and to determine information on the structure and function of chondrocyte perlecan. Perlecan is a prominent component of human fetal (12-14 week) finger, toe, knee, and elbow cartilages; it was localized diffusely in the interterritorial extracellular matrix, densely in the pericellular matrix around chondrocytes, and to small blood vessels in the joint capsules and perichondrium. Aggrecan had a more intense distribution in the marginal regions of the joint rudiments and in para-articular structures. Perlecan also had a strong pericellular localization pattern in postnatal (2-7 month) and mature (55-64 year) femoral cartilages, whereas aggrecan had a prominent extracellular matrix distribution in these tissues. Western blotting identified multiple perlecan core protein species in extracts of the postnatal and mature cartilages, some of which were substituted with heparan sulfate and/or chondroitin sulfate and some were devoid of glycosaminoglycan substitution. Some perlecan core proteins were smaller than intact perlecan, suggesting that proteolytic processing or alternative splicing had occurred. Surface plasmon resonance and quartz crystal microbalance with dissipation experiments demonstrated that chondrocyte perlecan bound fibroblast growth factor (FGF)-1 and -9 less efficiently than endothelial cell perlecan. The latter perlecan supported the proliferation of Baf-32 cells transfected with FGFR3c equally well with FGF-1 and -9, whereas chondrocyte perlecan only supported Baf-32 cell proliferation with FGF-9. The function of perlecan therefore may not be universal but may vary with its cellular origin and presumably its structure. The aim of this study was to immunolocalize perlecan in human fetal, postnatal, and mature hyaline cartilages and to determine information on the structure and function of chondrocyte perlecan. Perlecan is a prominent component of human fetal (12-14 week) finger, toe, knee, and elbow cartilages; it was localized diffusely in the interterritorial extracellular matrix, densely in the pericellular matrix around chondrocytes, and to small blood vessels in the joint capsules and perichondrium. Aggrecan had a more intense distribution in the marginal regions of the joint rudiments and in para-articular structures. Perlecan also had a strong pericellular localization pattern in postnatal (2-7 month) and mature (55-64 year) femoral cartilages, whereas aggrecan had a prominent extracellular matrix distribution in these tissues. Western blotting identified multiple perlecan core protein species in extracts of the postnatal and mature cartilages, some of which were substituted with heparan sulfate and/or chondroitin sulfate and some were devoid of glycosaminoglycan substitution. Some perlecan core proteins were smaller than intact perlecan, suggesting that proteolytic processing or alternative splicing had occurred. Surface plasmon resonance and quartz crystal microbalance with dissipation experiments demonstrated that chondrocyte perlecan bound fibroblast growth factor (FGF)-1 and -9 less efficiently than endothelial cell perlecan. The latter perlecan supported the proliferation of Baf-32 cells transfected with FGFR3c equally well with FGF-1 and -9, whereas chondrocyte perlecan only supported Baf-32 cell proliferation with FGF-9. The function of perlecan therefore may not be universal but may vary with its cellular origin and presumably its structure. Perlecan is a modular heparan sulfate (HS) 2The abbreviations used are: HS, heparan sulfate; CS, chondroitin sulfate; GAG, glycosaminoglycan; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; QCM-D, quartz crystal microbalance with dissipation monitoring; mAb, monoclonal antibody; PBS, phosphate-buffered saline; PRELP, proline/arginine-rich and leucine-rich repeat protein; BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; MOPS, 4-morpholineethanesulfonic acid. and/or chondroitin sulfate (CS)-substituted proteoglycan commonly but not exclusively associated with basement membranes (1Murdoch A.D. Liu B. Schwarting R. Tuan R.S. Iozzo R.V. J. Histochem. Cytochem. 1994; 42: 239-249Crossref PubMed Scopus (166) Google Scholar, 2Iozzo R.V. Cohen I.R. Grassel S. Murdoch A.D. Biochem. J. 1994; 302: 625-639Crossref PubMed Scopus (341) Google Scholar). The human perlecan gene, HSPG2, contains 97 exons (GenBank™ accession number NT_004576 (3Nicole S. Davoine C.S. Topaloglu H. Cattolico L. Barral D. Beighton P. Hamida C.B. Hammouda H. Cruaund C. White P.S. Samson D. Urtizberea J.A. Lehmann-Horn F. Weissenbach J. Hentati F. Fontaine B. Nat. Genet. 2000; 26: 480-483Crossref PubMed Scopus (227) Google Scholar)) and encodes a large 467-kDa protein core consisting of five distinct domains that display homology to the laminin A chain, low density lipoprotein receptor, neural cell adhesion molecule, and epidermal growth factor (4Noonan D.M. Fulle A. Nalente P. Cai S. Horigan E. Sasaki M. Yamada Y. Hassell J.R. J. Biol. Chem. 1991; 266: 22939-22947Abstract Full Text PDF PubMed Google Scholar, 6Murdoch A.D. Dodge G.R. Cohen I. Tuan R.S. Iozzo R.V. J. Biol. Chem. 1992; 267: 8544-8557Abstract Full Text PDF PubMed Google Scholar). Domain-I is the main region of glycosaminoglycan (GAG) substitution in human perlecan and contains a cluster of 3 potential attachment sites (7Kokenyesi R. Silbert J.E. Biochem. Biophys. Res. Commun. 1995; 211: 262-267Crossref PubMed Scopus (40) Google Scholar, 12Friedrich M.V. Göhring W. Mörgelin M. Brancaccio A. David G. Timpl R. J. Mol. Biol. 1999; 294: 259-270Crossref PubMed Scopus (75) Google Scholar). When substituted with HS, perlecan domain I promotes binding to laminin-1 and collagen IV. Perlecan can also interact with nidogen-2, fibulin-2, fibronectin, PRELP (proline/arginine-rich and leucine-rich repeat protein)/prolargin, and types XIII and XVIII collagen (13Sasaki T. Gohring W. Pan T-C. Chu M-L. Timpl R. J. Mol. Biol. 1995; 254: 892-899Crossref PubMed Scopus (108) Google Scholar, 19Miosge N. Simniok T. Sprysch P. Herken R. J. Histochem. Cytochem. 2003; 51: 285-296Crossref PubMed Scopus (63) Google Scholar). It is hardly surprising therefore that perlecan has important cell adhesive as well as structural and matrix organizational roles (15Hopf M. Göhring W. Mann K. Timpl R. J. Mol. Biol. 2001; 311: 529-541Crossref PubMed Scopus (75) Google Scholar, 16Salmivirta K. Talts J.F. Olsson M. Sasaki T. Timpl R. Ekblom P. Exp. Cell Res. 2002; 279: 188-201Crossref PubMed Scopus (90) Google Scholar, 18Bengtsson E. Mörgelin M. Sasaki T. Timpl R. Heinegard D. J. Biol. Chem. 2002; 277: 15061-15068Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 19Miosge N. Simniok T. Sprysch P. Herken R. J. Histochem. Cytochem. 2003; 51: 285-296Crossref PubMed Scopus (63) Google Scholar, 21Whitelock J.M. Graham L.D. Melrose J. Murdoch A.D. Iozzo R.V. Underwood A. Matrix Biol. 1999; 18: 163-178Crossref PubMed Scopus (122) Google Scholar). The HS side chains of domain I of perlecan act as low affinity co-receptors for growth factors, such as FGF-1, -2, -7, and -9, whereas the core protein of perlecan may act as a receptor for FGF-7 (22Chang Z. Meyer K. Rapraeger A.C. Friedl A. FASEB J. 2000; 14: 137-144Crossref PubMed Scopus (94) Google Scholar, 25Ghiselli G. Eichstetter I. Iozzo R.V. Biochem. J. 2001; 359: 153-163Crossref PubMed Scopus (37) Google Scholar). These interactions are important for the correct presentation of the FGFs to FGF receptors (FGFRs) and their subsequent oligomerization and activation, which initiates cell signaling and subsequent down-line effects on cell proliferation and differentiation (22Chang Z. Meyer K. Rapraeger A.C. Friedl A. FASEB J. 2000; 14: 137-144Crossref PubMed Scopus (94) Google Scholar, 27Knox S. Merry C. Stringer S. Melrose J. Whitelock J. J. Biol. Chem. 2002; 277: 14657-14665Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). Binding of the FGFs to perlecan also protects them from proteolytic degradation in situ and increases their biological half-life (22Chang Z. Meyer K. Rapraeger A.C. Friedl A. FASEB J. 2000; 14: 137-144Crossref PubMed Scopus (94) Google Scholar, 24Clayton A. Thomas J. Thomas G.J. Davies M. Steadman R. Kidney Int. 2001; 59: 2084-2094Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 28Whitelock J.M. Murdoch A.D. Iozzo R.V. Underwood P.A. J. Biol. Chem. 1996; 271: 10079-10086Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar, 29Iozzo R.V. J. Clin. Investig. 2001; 108: 165-167Crossref PubMed Scopus (233) Google Scholar). Connective tissue growth factor has also recently been shown to bind to the low density lipoprotein repeats within domain II of perlecan. Connective tissue growth factor modulates bone morphogenetic protein and transforming growth factor-β signaling and coordinates chondrogenesis and angiogenesis during skeletal B. Nat. Cell Biol. 2002; PubMed Scopus Google Scholar, Cell PubMed Scopus Google Scholar). The of perlecan has the that perlecan in and M. E. A. M. W. E. K. Timpl R. R. J. Cell Biol. 1999; PubMed Scopus Google Scholar, K. T. J. J. Cell Biol. 1999; PubMed Scopus Google Scholar). which to display skeletal with and in the growth of their and growth are of and and the cellular within of these and the them are signaling perlecan the is in the and the growth is more than in M. E. A. M. W. E. K. Timpl R. R. J. Cell Biol. 1999; PubMed Scopus Google Scholar, B. J. Cell Biol. 1999; PubMed Scopus Google Scholar). in the human perlecan been identified in and the (3Nicole S. Davoine C.S. Topaloglu H. Cattolico L. Barral D. Beighton P. Hamida C.B. Hammouda H. Cruaund C. White P.S. Samson D. Urtizberea J.A. Lehmann-Horn F. Weissenbach J. Hentati F. Fontaine B. Nat. Genet. 2000; 26: 480-483Crossref PubMed Scopus (227) Google Scholar, E. N. P. Hassell J.R. Yamada Y. Nat. Genet. 2001; PubMed Scopus Google Scholar, S. 2003; PubMed Scopus Google Scholar). Perlecan has been in a of M. Iozzo R.V. PubMed Scopus Google perlecan in structural with human perlecan and its localization vary the Perlecan has been to the basement membranes of human (1Murdoch A.D. Liu B. Schwarting R. Tuan R.S. Iozzo R.V. J. Histochem. Cytochem. 1994; 42: 239-249Crossref PubMed Scopus (166) Google and human and which are devoid of basement membranes R.V. Cohen I.R. Grassel S. Murdoch A.D. Biochem. J. 1994; 302: 625-639Crossref PubMed Scopus (341) Google Scholar). perlecan has been in human and M. E. A. M. W. E. K. Timpl R. R. J. Cell Biol. 1999; PubMed Scopus Google Scholar, N. D. S. S. Hassell J.R. J. Cell 1995; 108: PubMed Google growth and of the of the fetal human and growth and cartilages with J. Whitelock Histochem. Cell Biol. 2002; PubMed Scopus Google Scholar, J. S. M. R. Whitelock J. Histochem. Cell Biol. PubMed Scopus Google Scholar). its to tissue growth and perlecan has to be in in human The study was to determine the distribution and structure of perlecan in human during fetal in the and in the mature human was to to large for the of human chondrocyte perlecan for on growth factor perlecan was from human endothelial cell and chondrocyte and used to study the with FGF-1 and -9 and its on cell of was from to intact HS and to the the of were from to perlecan domain was from and to perlecan domains I and were used as J.M. Graham L.D. Melrose J. Murdoch A.D. Iozzo R.V. Underwood A. Matrix Biol. 1999; 18: 163-178Crossref PubMed Scopus (122) Google Scholar, J. Whitelock Histochem. Cell Biol. 2002; PubMed Scopus Google Scholar, J. S. M. R. Whitelock J. Histochem. Cell Biol. PubMed Scopus Google Scholar). to the domain of aggrecan was from protein and were from of for human were of the of the were for 3 in for perlecan or for aggrecan and in acid. human femoral was with the of from the and the were in in PBS, The were in and in to were in the and and on in and to tissue were with to and with and to cellular to of the for was the tissue with tissue were with for in in were with for in binding was the in or for with to perlecan domains I or and aggrecan domain were for or or were for was with and in or with were also in which or was substituted for the of that is in was used for this and was small and with of in the of White J. Biol. Chem. Full Text PDF PubMed Google Scholar). were and of the was with and/or and I for 3 Perlecan core proteins were on in or in the were membranes with and protein were also for and and were used as A was used as the of the and subsequent to were also used with the for in some and of Perlecan from were from and as J. S. P. J. 2002; PubMed Scopus Google and in in with fetal and The was and cell growth had the cells were and had A of of was from the and chondrocyte Perlecan was from the a of and J.M. Iozzo R.V. Cell Biol. 2002; PubMed Scopus Google Scholar). cell perlecan was also in a as J.M. Graham L.D. Melrose J. Murdoch A.D. Iozzo R.V. Underwood A. Matrix Biol. 1999; 18: 163-178Crossref PubMed Scopus (122) Google Scholar, S. Melrose J. Whitelock J. 2001; PubMed Scopus (40) Google Scholar, 27Knox S. Merry C. Stringer S. Melrose J. Whitelock J. J. Biol. Chem. 2002; 277: 14657-14665Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). of Perlecan with FGF-1 and Surface perlecan from the chondrocyte and human endothelial cell were in a of for 3 was the of of and was from the S. Melrose J. Whitelock J. 2001; PubMed Scopus (40) Google Scholar, 27Knox S. Merry C. Stringer S. Melrose J. Whitelock J. J. Biol. Chem. 2002; 277: 14657-14665Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). perlecan in were to a of A of perlecan was to the in as from the in which with a in of the binding experiments with FGF-1 and were in a of of The function was used with a of the perlecan was a of or were were with for the of the binding and experiments were also with perlecan that had been with to of Perlecan with FGF-1 and with in were quartz a of for for for in was to the for to binding sites with for Binding of FGF-1 and was in in a of for with for and for to growth factor were in The M. F. A. P. B. 1995; Scopus Google and dissipation during the and were the to The that the is of and its and not M.V. M. M. B. 1999; 59: Scopus Google Scholar). of in Cell of perlecan to cell proliferation was in a cell that the signaling of FGFs their receptors S. Merry C. Stringer S. Melrose J. Whitelock J. J. Biol. Chem. 2002; 277: 14657-14665Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, D.M. N. Biol. 2001; Google Scholar). Baf-32 cells that not heparan sulfate and are transfected with the receptor D. were in with fetal from cells from the and were as and D.M. N. Biol. 2001; Google and S. Melrose J. Whitelock J. 2001; PubMed Scopus (40) Google Scholar, 27Knox S. Merry C. Stringer S. Melrose J. Whitelock J. J. Biol. Chem. 2002; 277: 14657-14665Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). Baf-32 cells were in fetal and a density of The were to a of with FGF-1, or and perlecan to of for FGF-1 or -9, for and for the The cells were for of in and and of in of was well and the cells a The cells were for and the from the to was and the cells were in and to of and the on experiments were also with perlecan that had been with to HS Perlecan was in a number of fetal human the and of the and rudiments of the elbow and femoral and of the fetal and postnatal cartilages Perlecan was a prominent extracellular matrix component of the and rudiments and it was a prominent pericellular component of the growth and Perlecan in these were to the distribution of proteoglycan with it was not localized the joint Perlecan was also associated with small and in the and of the and Aggrecan was localized the of the rudiments in the and not display as a distribution the as perlecan Perlecan also had a distribution in the rudiments of the fetal elbow and was associated with small blood vessels in the of the joint capsules and and the joint it was associated with prominent small and of perlecan domain I aggrecan domain and proteoglycan in of the rudiments of a human fetal week) the is to the and the to the side of the Perlecan has a matrix and a strong pericellular distribution pattern the of the fetal human elbow has extracellular distribution pattern and is also localized in and in the elbow joint are in these and to the are in and is a of the in of proteoglycan aggrecan and perlecan and in of a and and and fetal human The femoral and are in the Perlecan a distribution the rudiments their and aggrecan a more distribution in the rudiments and was also its perlecan was a and to that used in the aggrecan and perlecan is in of the in are in These a prominent of blood vessels on the of the femoral in of small blood vessels the regions of the in are also with perlecan domain I as are regions of the femoral and the regions 3 in the femoral and that joint cells of a that not for perlecan are in and localization of perlecan in postnatal femoral from and and The shown perlecan domain were also domain and domain I not Aggrecan was also localized monoclonal to the domain of the aggrecan core protein Aggrecan is the extracellular matrix and in to the pericellular localization of perlecan with are the Perlecan was also prominent in the pericellular of the of postnatal and but was in the more was in the cell density is The pericellular of perlecan was of the domain of the used for and with the more for in pericellular aggrecan was also The cell density of for the of perlecan in Western blotting of extracts and with the of the perlecan and the of HS and substitution core proteins of be or The core protein was with the intact perlecan core whereas the smaller may be to proteolytic processing or alternative When was that the on the core protein of it was that the of the core proteins and for Western blotting of extracts of and on to domains I and of perlecan identified a number of core protein species of the perlecan core protein species were also the of HS substitution. were from a to the protein human endothelial cell perlecan as a core protein that was and in The of the human perlecan core protein species from to their were in the perlecan than in was also in the Perlecan was a species in the only and from perlecan domain I it was it was not it may a of domain I devoid of the HS attachment perlecan core protein species of from to were identified and that these may be of domain I perlecan core Surface plasmon resonance that bound of FGF-1 and whereas the chondrocyte perlecan bound well to but to FGF-1 The of growth to was with The was for suggesting that the affinity for this growth factor be The binding of FGF-1 to chondrocyte perlecan not be of HS as the chondrocyte perlecan was with the in not the binding of endothelial and perlecan are experiments with perlecan that had been with to HS that growth factor binding was HS for perlecan not The quartz crystal microbalance the plasmon resonance that that endothelial perlecan bound growth FGF-1 and more efficiently than chondrocyte perlecan a and was the of FGF-1 and binding to chondrocyte perlecan as was plasmon in dissipation the to in the of the for FGF-1 and binding to perlecan was the of the FGF-1 and binding to chondrocyte perlecan was more than binding to endothelial perlecan suggesting that are in growth factor binding endothelial and perlecan and that the chondrocyte perlecan the FGFs less supported the proliferation of Baf-32 cells FGF-1 and FGF-9. FGF-1 was with chondrocyte perlecan in this whereas cell proliferation with was to the with endothelial cell perlecan supported the of perlecan to interact with these growth in plasmon resonance and experiments and perlecan not cellular proliferation not which is with a of FGF-1 and -9 binding the in plasmon resonance Perlecan was extracellular component of the rudiments and a prominent pericellular component of growth in joint cartilages of the and knee, which is in with its in chondrogenesis R.V. Cohen I.R. Grassel S. Murdoch A.D. Biochem. J. 1994; 302: 625-639Crossref PubMed Scopus (341) Google Scholar, 29Iozzo R.V. J. Clin. Investig. 2001; 108: 165-167Crossref PubMed Scopus (233) Google Scholar, Cell PubMed Scopus Google Scholar, E. H. H. Hassell J.R. Yamada Y. Nat. Genet. 1999; PubMed Scopus Google Scholar, K. T. J. J. Cell Biol. 1999; PubMed Scopus Google Scholar, N. D. S. S. Hassell J.R. J. Cell 1995; 108: PubMed Google Scholar). Perlecan pattern that more with the of the rudiments than aggrecan suggesting that perlecan may a more of chondrogenesis than aggrecan in cartilages and also that these may roles in these its extracellular matrix localization aggrecan also in some of the in this is with the pericellular distribution demonstrated for aggrecan in J.M. Matrix Biol. 2002; PubMed Scopus Google Scholar). study has also shown that the pericellular localization of perlecan in human and that perlecan may be in that are devoid of GAG, HS or CS, or are with HS and The of HS and substitution has been on perlecan from the growth P. L. P. K. Hassell J.R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). attachment sites been in domains I (7Kokenyesi R. Silbert J.E. Biochem. Biophys. Res. Commun. 1995; 211: 262-267Crossref PubMed Scopus (40) Google Scholar, 12Friedrich M.V. Göhring W. Mörgelin M. Brancaccio A. David G. Timpl R. J. Mol. Biol. 1999; 294: 259-270Crossref PubMed Scopus (75) Google and P. Hassell J.R. B. J.R. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google Scholar, 12Friedrich M.V. Göhring W. Mörgelin M. Brancaccio A. David G. Timpl R. J. Mol. Biol. 1999; 294: 259-270Crossref PubMed Scopus (75) Google Scholar, Sasaki T. Gohring W. Yamada Y. Timpl R. J. Biochem. PubMed Scopus Google of perlecan, with such sites in domains I and II in domain it is not substitution in domain is to domains may be substituted with HS or of perlecan also been in M. H. R. S. M. L. N. B. K. R. J. 2003; PubMed Scopus Google Scholar). the of and the of substitution the of perlecan S. Melrose J. Whitelock J. 2001; PubMed Scopus (40) Google Scholar, 27Knox S. Merry C. Stringer S. Melrose J. Whitelock J. J. Biol. Chem. 2002; 277: 14657-14665Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). it is not the cell can its substitution or in a tissue the pattern of substitution. It is also that perlecan core proteins of are in the The human perlecan 97 exons accession number and is therefore potential for core protein to alternative is some for such G. J. D. Res. 2002; the of core protein in the study is proteolytic It is to that the sites of substitution in perlecan domains I and the of the intact core proteolytic processing may sites for of the substitution with HS or CS, that potential sites are equally to substitution. perlecan core protein species were in the extracts in this species also been in M. S. W. Matrix Biol. PubMed Scopus Google Scholar). The of these core protein species was in the mature perlecan core protein species were identified in the human extracts from the and these in from to A number of demonstrated a of perlecan core protein species of to identified in the study in endothelial J.M. Murdoch A.D. Iozzo R.V. Underwood P.A. J. Biol. Chem. 1996; 271: 10079-10086Abstract Full Text Full Text PDF PubMed Scopus (518) Google P. S. J.R. Biochem. J. 2001; PubMed Google and cells J. Whitelock J. P. J. Full Text Full Text PDF PubMed Scopus Google and in bone D. Biochem. J. 1999; PubMed Google and S. K. Melrose J. Whitelock J. PubMed Scopus Google Scholar). core protein species are also in human I. M. N. A. Biochem. J. 1999; PubMed Scopus Google Scholar). a perlecan core protein has been from human in T. K. I. M. K. N. Clin. 1996; PubMed Scopus Google and a from domain of perlecan M. S. W. Matrix Biol. PubMed Scopus Google has been and that perlecan may be in Matrix and are of perlecan J.M. Murdoch A.D. Iozzo R.V. Underwood P.A. J. Biol. Chem. 1996; 271: 10079-10086Abstract Full Text Full Text PDF PubMed Scopus (518) Google and also been shown to be in cells from Melrose J. P. M. J. 1996; Full Text Full Text PDF PubMed Scopus Google and in M. L. T. J.R. Hassell J.R. A.D. K. J. 2001; PubMed Scopus Google Scholar). The of perlecan in the of and (3Nicole S. Davoine C.S. Topaloglu H. Cattolico L. Barral D. Beighton P. Hamida C.B. Hammouda H. Cruaund C. White P.S. Samson D. Urtizberea J.A. Lehmann-Horn F. Weissenbach J. Hentati F. Fontaine B. Nat. Genet. 2000; 26: 480-483Crossref PubMed Scopus (227) Google Scholar, M. E. A. M. W. E. K. Timpl R. R. J. Cell Biol. 1999; PubMed Scopus Google Scholar, E. Yamada Y. J. Genet. 2001; PubMed Scopus Google Scholar, B. J. Cell Biol. 1999; PubMed Scopus Google Scholar, S. 2003; PubMed Scopus Google on and function the of this proteoglycan in the pericellular It has been shown that perlecan can interact with of the extracellular matrix core protein (15Hopf M. Göhring W. Mann K. Timpl R. J. Mol. Biol. 2001; 311: 529-541Crossref PubMed Scopus (75) Google Scholar, M. J. R. R. Iozzo R.V. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google or HS E. Mörgelin M. Sasaki T. Timpl R. Heinegard D. J. Biol. Chem. 2002; 277: 15061-15068Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, S. Melrose J. Whitelock J. 2001; PubMed Scopus (40) Google Scholar, 28Whitelock J.M. Murdoch A.D. Iozzo R.V. Underwood P.A. J. Biol. Chem. 1996; 271: 10079-10086Abstract Full Text Full Text PDF PubMed Scopus (518) Google are the interactions of the HS with FGF S. Melrose J. Whitelock J. 2001; PubMed Scopus (40) Google Scholar, 28Whitelock J.M. Murdoch A.D. Iozzo R.V. Underwood P.A. J. Biol. Chem. 1996; 271: 10079-10086Abstract Full Text Full Text PDF PubMed Scopus (518) Google and PRELP E. Mörgelin M. Sasaki T. Timpl R. Heinegard D. J. Biol. Chem. 2002; 277: 15061-15068Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). The may cell and the latter may a the pericellular matrix and the more FGF PRELP with CS, which the of of perlecan the in the The growth factor binding and cell proliferation on the of perlecan with FGFs that perlecan vary in function S. Merry C. Stringer S. Melrose J. Whitelock J. J. Biol. Chem. 2002; 277: 14657-14665Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). the it be important to the of HS or or in sites and and the of perlecan roles in and mature

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