Proteoglycan-Collagen XV in Human Tissues Is Seen Linking Banded Collagen Fibers Subjacent to the Basement Membrane
Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical SchoolUMDNJ, New Brunswick, New Jersey (PSA,NAS,MDN,JPS) and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (DL,JCM)
Correspondence to: Jeanne C. Myers, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 909 Stellar Chance, Philadelphia, PA 19104-6059. E-mail: myers{at}mail.med.upenn.edu
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Summary |
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Key Words: type XV collagen extracellular matrix basement membrane non-fibrillar proteoglycan heparan sulfate chondroitin sulfate immunogold electron microscopy
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Introduction |
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The type XV collagen chain is comprised of 1363 residues (Myers et al. 1992; Kivirikko et al. 1994
, and Figure 1)
. Most of the sequence is non-collagenous and represented in the 530 and 256 residue amino and carboxy domains, respectively. The 577 residue discontinuous collagenous region is highly interrupted by many different-size non-collagenous segments, totaling one-third of the domain sequences. RNA analysis by in situ hybridization and northern blotting showed that type XV is expressed by fibroblast, muscle, endothelial and some epithelial cells (Kivirikko et al. 1995
) and is detected in most tissues except for liver and brain (Myers et al. 1996
). Consistent with these observations, light microscopy immunohistochemistry illustrated a nearly ubiquitous type XV distribution in human tissues, but a restricted localization in most epithelial, and all nerve, muscle, fat and endothelial BM zones, except for those of the glomerular capillaries or hepatic/splenic sinusoids (Myers et al. 1996
,1997
; Hagg et al. 1997
; Tomono et al. 2002
). There was minimal type XV immunoreactivity in the interstitium. Type XV collagen in vivo is a full-time proteoglycan (PG) with a mass of glycosaminoglycan (GAG) chains attached to the N-terminal domain (Li et al. 2000
). Digestion with chondroitinase, but not heparitinase, revealed type XV core protein chains of 250/225 kD, which are subject to some degree of carboxy-terminal cleavage. Partial purification of type XV from placenta showed that in the richest source of this collagen, it is a very scarce and very large protein (greater than 1 million molecular weight).
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Materials and Methods |
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Electron Microscopy Immunohistochemistry
Normal human tissues were acquired from the Department of Pathology and Laboratory Medicine at Robert Wood Johnson University Hospital. Three or four experiments were conducted using each tissue. Immunogold localization was carried out with modifications of the procedure reported by Birk et al. (1988). Tissues were minced into small pieces and fixed in 4% paraformaldehyde in 0.2 M sodium phosphate buffer, pH 7.4, for 1012 min. They were then washed at 4C in 4% sucrose in PBS for 1 hr, followed by 7% glycerol/4% sucrose in PBS for 1 hr. The tissues were snap-frozen in OCT compound (Miles Inc.; Elkhart, IN) in methylbutane at liquid nitrogen temperature and stored at 80C until sectioning. Five-µm sections were prepared on a cryostat at 20C onto poly-L-lysine-coated slides, dried at room temperature, and rehydrated with cold PBS at 4C. Tissue sections were treated with 0.1 mg/ml testicular hyaluronidase (Sigma-Aldrich; St Louis, MO) for 1 hr at 37C, washed in cold PBS, reduced with 0.25 mg/ml sodium borohydride for 15 min and rinsed again in PBS. Chondroitinase ABC (Seikagako Corp.; Rockville, MD) pretreatment (0.2 units/ml at 37C overnight) was included in some initial experiments but later discontinued since it did not change the final results. Sections were pretreated with 5% bovine serum albumin (BSA) in PBS for 1 hr at room temperature and then incubated with purified type XV polyclonal carboxy or amino antibodies (14 µg/ml and 44 µg/ml, respectively) overnight in a humidified chamber at 4C. In the control samples included with each experiment, kidney, placenta and colon tissue sections were incubated with normal rabbit serum or buffer in place of the primary antibody. Slides were rinsed in cold PBS and 1% Tween 20 and incubated as above with 6 nm gold-labeled goat anti-rabbit IgG (Electron Microscopy Sciences; Fort Washington, PA) at a 1:2.5 dilution in 1% BSA. The tissues were fixed with 2.5% glutaraldehyde in 0.1 M sodium cacodylate, pH 7.4, for 15 min, rinsed in the same buffer and treated with 1% osmium tetroxide for 1 hr. The slides were washed with 50% ethanol and dehydrated through an increasing concentration gradient of alcohol and acetone to a final concentration of 100% acetone. The sections were subsequently embedded in epon resin, sectioned and viewed on a Jeol 1200S electron microscope.
Tissue Extracts, Enzyme Digestions and Immunoblotting
Normal human tissues were obtained from the Hospital of the University of Pennsylvania and Robert Wood Johnson University Hospital. Samples were stored at 80C and thawed at 4C or in an ice slurry. One to three grams of tissue were minced and added to 10 vol of extraction buffer (50 mM Tris-HCl, 1.0 M NaCl, 10 mM EDTA, pH 7.5) with protease inhibitors (10 mM N-ethylmaleimide, 0.5 mM phenylmethylsulfonyl fluoride, 5 µg/ml leupeptin, 1 µg/ml aprotinin, obtained from Sigma). The tissues were homogenized at speed 5 (speed 7 = 27,000 rpm) for 8 x 1 min (Polytron; Brinkman Instruments, Westbury, NY) while maintained in an ice slurry. The tissue suspensions were rocked overnight at 4C and centrifuged at 32,500 x g for 30 min at 4C. The supernatant was dialyzed against 50 mM Tris-HCl, 1 mM EDTA, 100 mM NaCl, pH 7.5, plus protease inhibitors. Samples were aliquoted and stored at 80C. Protein concentrations were determined using the BCA reagent (Pierce Biotechnology; Rockford, IL).
The amount of protein extract used for the reactions was as follows: kidney, 44 µg; colon, 28 µg; and placenta, 15 µg. The control samples for the enzyme reactions were incubated exactly as described below but without any glycosidase. Three types of enzyme reactions were carried out: chondroitinase alone [designated R1ch]; chondroitinase and then heparitinase [designated R2ch+hep]; and heparitinase alone [designated R3hep]. All reactions contained the same volume and buffer concentrations and were incubated for the same time and temperature. The first incubation (chondroitinase reaction conditions) was carried out in 15 µl at 37C for 90 min, and the second incubation (heparitinase reaction conditions) was carried out in 24 µl at 43C for 90 min. In the first reaction, 3 µl of 5x buffer was added to give a final concentration of 100 mM Tris-HCl, 30 mM sodium acetate buffer, pH 7.4. [R1ch] and [R2ch+hep] reactions contained 3 µl (30 milliunits) of chondroitinase ABC (Sigma-Aldrich); [R3hep] reactions contained no chondroitinase. After the first incubation, 5 µl of 5x buffer (0.5 M sodium acetate, 50 mM calcium acetate, pH 7.0) was added to each reaction for the second incubation. To [R2ch+hep] and [R3hep] reactions, 4 µl (4 milliunits) of heparitinase (mixture of form I and form II) (Seikagako Corp.; Rockville, MD) was added. To [R1ch] reactions lacking heparitinase, 4 µl of water was added. (In other experiments, a second 90 min incubation was carried out for [R1ch] reactions in which another 30 milliunits of chondroitinase was added. There was no difference in the signal intensity for the type XV bands compared with reactions incubated for the single 90 min duration.)
The samples were boiled for 2 min in 60 mM Tris-HCl, pH 6.8, 4% SDS, 10% glycerol, 50 mM EDTA, 0.025% bromophenol blue, 100 mM DTT and electrophoresed in a 8% SDS-polyacrylamide gel containing 0.05% N, N'-methylene-bis-acrylamide. Immunoblotting has been described previously (Myers et al. 1996). Membranes were incubated for 90 min with the type XV polyclonal carboxy antibody at a concentration of 0.22 µg/ml, washed and incubated with a 1:5000 dilution of secondary antibody (anti-rabbit IgG, peroxidase-linked F(ab')2 fragment from donkey (Amersham Bioscience; Piscataway, NJ). Membranes were developed using ECL reagents (Amersham).
Line densitometry quantitation of bands was determined on several films for each tissue set using the FluorChem 8800 Imaging System (Alpha Innotech Corp.; San Leandro, CA).
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Results |
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By light microscopy (Myers et al. 1996,1997
), type XV collagen had been found in the renal capsular, vascular, smooth muscle, neural and lipocyte BM zones, but was virtually absent from the glomerular capillaries, mesangium, and the tubular BM zone, except when adjacent to interstitial capillaries or the glomerular capsule. In placenta, all BM zones, i.e., trophoblastic, vascular, and smooth muscle BM zones of the chorionic villi were reactive for type XV. Similarly, all BM zones in colon stained positive for type XV including the colonic surface epithelial and crypt BM zones.
Immunogold Localization of Type XV Collagen in Human Tissues
Kidney
The gold particles marking the ultrastructural localization of type XV collagen were concentrated beneath the endothelial BM (Figure 2A)
and the epithelial BM of the glomerular capsule (Figure 2B). The BM proper of the glomerulus, vascular endothelium and epithelium was essentially devoid of particles except for an occasional few at the interface with the underlying stroma. Most type XV was found in association with thick-banded collagen fibers of 35+ nm in diameter, immediately adjacent and/or inserting into the BM. The type XV particles occurred in clusters or linear arrays; they spanned the width of a fiber or fibers, extended laterally, and formed a bridge between two or more fibers.
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Discussion |
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The predominant localization of type XV in kidney, placenta and colon was consistently in the collagen network of fibers just distal to epithelial and endothelial BMs. The occasional gold particles within the outermost aspect of the BM may reflect a real type XV presence or original sites of contact between the BM and focally inserted fibers coated with type XV. In all three tissues, gold particles were identified in linear arrays and in clusters along the surface of banded 35+ nm diameter collagen fibers and in some cases, also thinner 1015 nm fibrils. Type XV particles projecting laterally from one fiber were usually in close apposition to another. Organized type XV bridges linking fibers were striking in appearance and a common finding. These
30- to 90-nm-length formations may be a direct consequence of type XV assembly or another matrix protein(s) and visualized here because of the type XV association. Future knowledge of the type XV supramolecular conformation may help to clarify these questions. Use of both type XV amino- and carboxy-domain antibodies showed no difference in orientation of the gold particles. Notably, partial purification of type XV under non-denaturing vs denaturing conditions revealed approximately three times less protein was extracted in the neutral salt buffer, supporting an intricate association of this molecule in the fibrillar collagen matrix (Li et al. 2000
and unpublished data).
Type XV Has a Distinctly Different Distribution from Its Homolog, Type XVIII Collagen
This report helps to resolve the long-standing confusion of the relationship between types XV and XVIII collagen. The homology in primary structure, and their localization to BM zonesalbeit different in some tissues especially livercaused much speculation that these two collagens may have similar roles (Myers et al. 1996,1997
; Hagg et al. 1997
; Saarela et al. 1998
). An additional parallel was drawn when they were discovered to be full time PGs (Halfter et al 1998
; Li et al. 2000
), a unique feature in the collagen family. But an important distinction was the nature of the GAG side chainsHS for type XVIII, vs CS for type XV or a mixture of both chains. Genetic data first provided evidence that the two collagens evolved to assume different functions. Null mice for the respective genes exhibit a very different phenotype and double deficient mice demonstrated the absence of biological compensation (Eklund et al. 2001
; Fukai et al. 2002
; Ylikarppa et al. 2003
). The type XVIII / mice have ocular abnormalities (consistent with human mutations, Sertie et al. 2000
) due to abnormal retinal pigment epithelia, whereas type XV / mice have stress-induced muscle and vascular defects and morphologically normal BM.
The ultrastructural analysis puts much of the data into perspective. Type XVIII collagen localizes in epidermal and vascular BM (Marneros et al. 2004), in accord with other HSPGs that are found in BM and in close proximity to the cell surface (Iozzo 2000
). The presence of type XV peripheral to BM and its association with collagen fibers/fibrils reflects primary glycanation with CS chains, since CSPGs are usually located in the stroma and have in a number of instances been shown to bind to fibrillar collagens (Iozzo 1999
; Ezura et al. 2000
). The distinct distribution also suggests that a putative type XV carboxy cleavage fragment, analogous to the type XVIII BM endostatin (O'Reilly et al. 1997
; Sasaki et al. 2000
) may have its own special function and a non-BM distribution like its parent molecule.
Type XV May Help to Protect Collagen Fibers from Proteolysis
The localization of type XV collagen clarifies former light microscopy studies, which showed its distribution in colon and breast carcinomas to be significantly different from integral BM components (Amenta et al. 2000,2003
). Type XV was lost from the BM zone early in the invasive process, before fragmentation of the BM as evidenced by linear immunoreactivity for type IV collagen and laminin. This result suggested type XV was more sensitive to proteolysis, and/or was peripheral to the BM and exposed to a stromal environment where matrix metalloproteinases are upregulated in response to soluble factors released by tumor cells (Shapiro 1998
). One can now hypothesize that type XV may represent the first line of defense against matrix proteolysis and initially serve to protect type I/III/V collagen fibers from degradation, analogous to the aggregan-type II collagen relationship (Pratta et al. 2003
). Once the type XV structure is compromised, it may signal disruption first of the fibrillar collagen network and then of the collagenous-BM interface to facilitate tumor growth and cell migration. Additionally, type XV protein core fragments may possess biological activity, as well as the liberated GAG chain fragments, depending on the CS or HS content. Better understanding of the type XV function in normal tissue could well emerge from ultrastructural study of the type XV-fiber linkages at the in situ stage of tumor progression.
Type XV Displays Features Intermediate between Interstitial and BM Collagen Proteoglycans
Five collagens, IX, XII, XIV, XV and XVIII, are recognized as PGs. The first three are part-time CSPGs (Ricard-Blum et al. 2000); type XV is a CSPG or CS/HSPG hybrid (Li et al. 2000
, and Figure 6) and type XVIII in vivo is a HSPG (Halfter et al. 1998
) although in vitro it is decorated with both HS and CS chains (Dong et al. 2003
). Type IX is covalently linked to type II collagen fibers in cartilage (van der Rest and Mayne 1988
), types XII and XIV are associated with type I collagen bundles (van der Rest and Dublet 1996
; Keene et al. 1991
), and type XVIII is found in BM (Marneros et al. 2004
). Type XV exhibits properties of both groups, seeming to reflect its "intermediate" localization. Like types IX, XII and XIV, type XV is primarily associated with large banded collagen fibers, exists as a CSPG, and is present in the stroma. Like type XVIII, type XV is a full-time PG, can harbor HS side chains, and is present in the BM zone, but probably not BM per se. These features further emphasize the importance of CS chains in the interaction with collagen fibers and the importance of HS chains in BM/zone structure and biological activity.
Type XV Collagen Is Extensively Glycanated with Heparan Sulfate as well as Chondroitin Sulfate Chains
Whereas most HSPGs are known to carry CS chains (Iozzo 2000), to our knowledge the converse is not typical. Type XV is a CSPG that carries HS chains (Li et al. 2000
, Figure 6, and unpublished data); moreover, the ratio varies depending on the tissue. There are eight potential sites for GAG chain attachment in the type XV amino-terminus and three in the first interruption (Li et al. 2000
and Figure 1), but in vivo identification of occupancy and GAG chain characterization will likely be precluded by the paucity of type XV in tissues. We had estimated that glycosylation added a minimum of 200-kD mass to each individual 225/250 kD type XV chain (Li et al. 2000
). Compared with placenta and colon, the glycosylated kidney type XV chain is even larger than 400 kD and contains considerably more HS than CS chains. As with other PGs, the significance of type XV GAG forms, qualitatively and quantitatively, will be difficult to grasp until at least some model system is established. One would expect that the different forms are synthesized by different cell types recognized by different ligands and modulate different activities, as shown for two transmembrane syndecan-HSPGs that are also modified by CS chains (Carey 1997
; Yoneda and Couchman 2003
). It has recently been reported in fact that CS chains in syndecans-1 and -4 can "cooperate" with HS chains to bind growth factors for "delivery to the cell surface receptors" (Deepa et al. 2004
).
Concluding Remarks
Type XV joins the three well-known non-fibrillar collagen-CSPGs closely associated with collagen fibers. Type IX is thought to mediate interactions between collagen fibrils and the surrounding matrix, type XII has a presumed role in development of stromal architecture and maintenance of fibril organization, and type XIV is believed to help regulate fibrillogenesis (Bateman 2001; Young et al. 2002
). These still general statements could extend to type XV and it may be meaningful that the type XV immunogold profile looks similar to that of type XIV in human tendon (Keene et al. 1991
). However, only type XV is associated with a restricted collagenous network subjacent to BM and a loose rather than dense array of large collagen fibrils (likely types I, III). There were occasions when smaller fibrils (possibly collagen VI, fibrillin, etc., Keene et al. 1997
,1998
) were also seen in close proximity to type XV, especially in the portal area of the liver (data not shown). Future determination of their composition will help define interactions between the BM and the heterogeneous underlying stroma (Adachi et al. 1997
). Furthermore, the shift in CS to CS/HS modification of the type XV core protein may fundamentally change the properties of the molecule and of the matrix, not only among different tissues but also in epithelial/vascular/muscle BM zones of the same tissue. For example, type XV is strikingly absent from the glomerular capillaries, renal tubules and hepatic/splenic sinusoids where a reduced anionic charge in the environment enhances the filtering exchange (Kanwar et al. 1980
; Barnes et al. 1984
). This suggests type XV may also be important in maintaining a hydrated matrix that facilitates cell migration and in selectively modulating the transfer of soluble factors.
Type XV is clearly a multifunctional collagen-PG with different characteristics than originally believed. Our focus here has been on specific aspects of this novel molecule, which point already to its involvement in many biological processes and give a validated direction for future studies.
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Acknowledgments |
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We would like to thank Kelly Walton for excellent technical assistance, Rajesh Patel for extensive effort in the electron microscopy photography, and Mary Leonard for valuable help with the illustrations. We are very grateful to Dr David Birk at Thomas Jefferson University for advice on the immunogold procedures.
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Footnotes |
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Literature Cited |
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Adachi E, Hopkinson I, Hayashi T (1997) Basement-membrane stromal relationships: interactions between collagen fibrils and the lamina densa. Int Rev Cytol 173:73156[Medline]
Amenta PS, Briggs K, Xu K, Gamboa E, Jukkola AF, Li D, Myers JC (2000) Type XV collagen in human colonic adenocarcinomas has a different distribution than other basement membrane zone proteins. Hum Pathol 31:359366[Medline]
Amenta PS, Hadad S, Lee MT, Barnard N, Li D, Myers JC (2003) Loss of types XV and XIX collagen precedes basement membrane invasion in ductal carcinoma of the female breast. J Pathol 199:298308[CrossRef][Medline]
Barnes JL, Radnik RA, Gilchrist EP, Venkatachalam MA (1984) Size and charge selective permeability defects induced in glomerular basement membranes by a polycation. Kidney Int 25:1119[Medline]
Bateman JF (2001) The molecular genetics of inherited cartilage disease. Osteoarthritis Cartilage 9:S141S149[Medline]
Birk DE, Fitch JM, Babiarz JP, Linsenmayer TF (1988) Collagen type I and type V are present in the same fibrils in the avian corneal stroma. J Cell Biol 106:9991008[Abstract]
Carey DJ (1997) Syndecans: multifunctional cell-surface co-receptors. Biochem J 327:116[Medline]
Deepa SS, Yamada S, Zako M, Oldberger O, Sugahara K (2004) Chondroitin sulfate chains on syndecan-1 and syndecan-4 form normal murine mammary gland epithelial cells are structurally and functionally distinct and cooperate with heparan sulfate chains to bind growth factors. J Biol Chem 279:3736837376
Dong S, Cole GJ, Halfter W (2003) Expression of collagen XVIII and localization of its glycosaminoglycan attachment sites. J Biol Chem 278:17001707
Eklund L, Piuhola J, Komulainen J, Sormunen R, Ongvarrasopone C, Fassler R, Muona A, et al. (2001) Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice. Proc Natl Acad Sci USA 98:11941199
Erickson AC, Couchman JR (2000) Still more complexity in mammalian basement membranes. J Histochem Cytochem 48:12911306
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 151:779787
Fukai N, Eklund L, Marneros AG, Oh SP, Keene DR, Tamarkin L, Niemela M, et al. (2002) Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J 21:15351544
Ghohestani RF, Li K, Rousselle P, Uitto J (2001) Molecular organization of the cutaneous basement membrane zone. Clinics Dermatol 19:551562[CrossRef]
Hagg PM, Hagg PO, Peltonen S, Autio-Harmainen H, Pihlajaniemi T (1997) Location of type XV collagen in human tissues and its accumulation in the interstitial matrix of the fibrotic kidney. Am J Pathol 150:20752086[Abstract]
Halfter W, Dong S, Schurer B, Cole GJ (1998) Collagen XVIII is a basement membrane heparan sulfate proteoglycan. J Biol Chem 273:2540425412
Iozzo RV (1999) The biology of the small leucine-rich proteoglycans. J Biol Chem 274:1884318846
Iozzo RV (2000) Heparan sulfate proteoglycan: intricate molecules with intriguing functions. J Clin Invest 108:165167[CrossRef]
Kanwar YS, Linker A, Farquhar MG (1980) Increased permeability of the glomerular basement membrane to ferritin after removal of glycosaminoglycans (heparan sulfate) by enzyme digestion. J Cell Biol 86:688693[Abstract]
Keene DR, Lunstrom GP, Morris NP, Stoddard DW, Burgeson RE (1991) Two type XII-like collagens localize to the surface of banded collagen fibrils. J Cell Biol 113:971978[Abstract]
Keene DR, Jordan CD, Reinhardt DP, Ridgeway CC, Ono RN, Corson GM, Fairhurst M, et al. (1997) Fibrillin-1 in human cartilage: developmental expression and formation of special banded fibers. J Histochem Cytochem 45:10691082
Keene DR, Ridgway CC, Iozzo RV (1998) Type VI microfilaments interact with a specific region of banded collagen fibrils in skin. J Histochem Cytochem 46:215220
Kivirikko S, Heimamaki P, Rehn M, Honkanen N, Myers JC, Pihlajaniemi T (1994) Primary structure of the 1 chain of human type XV collagen and exon-intron organization in the 3' region of the corresponding gene. J Biol Chem 269:47734779
Kivirikko S, Saarela J, Myers JC, Autio-Harmainen H, Pihlajaniemi T (1995) Distribution of type XV collagen transcripts in human tissue and their production by muscle cells and fibroblasts. Am J Pathol 147:15001509[Abstract]
Li D, Clark CC, Myers JC (2000) Basement membrane zone type XV collagen is a disulfide-bonded chondroitin sulfate proteoglycan in human tissues and cultured cells. J Biol Chem 275:2233922347
Marneros AG, Keene DR, Hansen U, Fukai N, Moulton K, Goletz PL, Moiseyev G, et al. (2004) Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function. EMBO J 23:8999
Myers JC, Kivirikko S, Gordon MK, Dion AS, Pihlajaniemi T (1992) Identification of a previously unknown human collagen chain, 1(XV), characterized by extensive interruptions in the triple-helical region. Proc Natl Acad Sci USA 89:1014410148
Myers JC, Sun MJ, D'Ippolito JA, Jabs EW, Neilson EG, Dion AS (1993) Human cDNA clones transcribed from an unusually high-molecular-weight RNA encode a new collagen chain. Gene 123:211217[CrossRef][Medline]
Myers JC, Dion AS, Abraham V, Amenta PS (1996) Type XV collagen exhibits a widespread distribution in human tissues but a distinct localization in basement membrane zones. Cell Tissue Res 286:493505[CrossRef][Medline]
Myers JC, Li D, Bageris A, Abraham V, Dion AS, Amenta PS (1997) Biochemical and immunohistochemical characterization of human type XIX defines a novel class of basement membrane zone collagens. Am J Pathol 151:17291740[Abstract]
Oh SP, Kamagata Y, Muragaki Y, Timmons S, Ooshima A, Olsen BR (1994) Isolation and sequencing of cDNAs for proteins with multiple domains of Gly-Xaa-Yaa repeats identify a distinct family of collagenous proteins. Proc Natl Acad Sci USA 91:42294233
O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, et al. (1997) Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277285[Medline]
Pfendner EG, Nakano A, Pulkkinen L, Christiano AM, Uitto J (2003) Prenatal diagnosis for epidermolysis bullosa: A study of 144 consecutive pregnancies at risk. Prenatal Diagnosis. 23:447456[CrossRef][Medline]
Pratta MA, Yao W, Decicco C, Tortorella MD, Liu R-Q, Copeland RA, Magolda R, et al. (2003) Aggrecan protects cartilage collagen from proteolytic cleavage. J Biol Chem 278:4553945545
Ricard-Blum S, Dublet B, van der Rest M (2000) Unconventional Collagens. New York, Oxford University Press
Saarela J, Rehn M, Oikarinen A, Autio-Harmainen H, Pihlajaniemi T (1998) The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans. Am J Pathol 153:611626
Sakai LY, Keene DR, Morris NP, Burgeson RE (1986) Type VII collagen is a major structural component of anchoring fibrils. J Cell Biol 103:15771586[Abstract]
Sasaki T, Larsson H, Tisi D, Claesson-Welsh L, Hohenester E, Timpl R (2000) Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity. J Mol Biol 31:11791190
Sertie AL, Sossi V, Camargo AA, Zatz M, Brahe C, Passos-Bueno MR (2000) Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum Mol Genet 9:20512058
Shapiro SD (1998) Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Current Opin Cell Biol 10:602608[CrossRef][Medline]
Tomono Y, Naito I, Ando K, Yonezawa T, Sado Y, Hirakawa S, Arata J, et al. (2002) Epitope-defined monoclonal antibodies against multiplexin collagens demonstrate that type XV and XVIII collagens are expressed in specialized basement membranes. Cell Struct Funct 27:920[CrossRef][Medline]
van der Rest M, Mayne R (1988) Type IX collagen proteoglycan from cartilage is covalently cross-linked to type II collagen. J Biol Chem 263:16151618
van der Rest M, Dublet B (1996) Type XII and type XIV collagens: interfibrillar constituents of dense connective tissues. Cell Dev Biol 7:639648[CrossRef]
Ylikarppa R, Eklund L, Sormunen R, Muona A, Fukai N, Olsen BR, Pihlajaniemi T (2003) Double knockout mice reveal a lack of major functional compensation between collagens XV and XVIII. Matrix Biol 22:443448[CrossRef][Medline]
Yoneda A, Couchman JR (2003) Regulation of cytoskeletal organization by syndecan transmembrane proteoglycans. Matrix Biol 22:2533[CrossRef][Medline]
Young BB, Zhang G, Koch M, Birk DE (2002) The roles of types XII and XIV collagen in fibrillogenesis and matrix assembly in the developing cornea. J Cell Biochem 87:208220[CrossRef][Medline]
Yurchenco PD, Amenta PS, Patton BL (2004) Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol 22:521538[CrossRef][Medline]