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The collagens of the joint.

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In recent years, biochemical investigations have
shown that the various connective tissues in the human
organism are endowed with several different types of
collagen molecules ( 1). Isolation and characterization of
these genetically distinct collagens have provided considerable information on the physicochemical properties and biologic functions of these unique proteins. As
a consequence of these studies, we can currently delineate three classes of collagen molecules (Table 1):
interstitial collagen molecules, basement membrane collagens, and pericellular collagens.
The interstitial collagen molecules account for the
majority of the total body collagen. They occur
throughout the connective tissues in the form of fibrous
(often cross-striated) supporting elements (2). Included
in the class of interstitial collagens are: 1) the Type I
collagen molecule, a heteropolymer comprised of two
al(1) chains and an a2(I) chain, 2) the Type I-trimer
collagen molecule which is comprised of three al(1)
chains which appear to be identical to the al(1) chains
of the more prevalent Type I molecule; 3) the Type I1
collagen molecule comprised of three al(I1) chains; and
4) the Type 111 collagen molecule containing three
al(II1) chains.
The basement membrane collagens constitute the
second class of collagen molecules. Basement memFrom the University of Alabama in Birmingham, Medical
Center, Birmingham, Alabama.
Steffen Gay, MD: Associate Professor of Medicine, Division
of Clinical Immunology and Rheumatology, Department of Medicine; Renate E. Gay, MD: Research Associate, Institute of Dental Research; Edward J. Miller, PhD: Professor of Biochemistry, Department of Biochemistry.
Address reprint requests to Steffen Gay, MD, Division of
Clinical Immunology and Rheumatology, Department of Medicine,
University of Alabama in Birmingham, Birmingham, Alabama 35294.
Arthritis and Rheumatism, Vol. 23, No. 8 (August 1980)
brane collagen is commonly referred to as Type IV collagen, based on the notion that basement membrane
collagen molecules are comprised of only a single type
of chain (3). Nevertheless, more recent studies on the
collagenous constituents isolated from epithelial basement membrane have indicated the presence of at least
two distinct collagen chains, al(1V) and a2(IV), which
more than likely occur in separate molecular species
(4,5). The latter chains have also been identified in select fractions of the collagen extracted from highly vascularized tissue (6-8) and a basement membrane tumor
(9). Relative to the chains comprising the interstitial collagens, the al(1V) and a2(IV) chains exhibit several
unique compositional features. One of the more striking
of these features is a large decrease in the number of
alanyl residues per chain and a dramatic increase in the
number of the larger hydrophobic amino acids. The
al(1V) chain represents more than one-half of the collagenous components isolated from basement membrane
preparations and appears to be widely distributed in a
variety of basement membranes, since purified antibodies to the chain react specifically with basement
membrane structures in human skin (10).
The pericellular collagens constitute yet another
class of collagen molecules. Although these collagens
are commonly referred to as Type V collagen, it is quite
clear that they may contain collectively as many as
three distinct collagen chains, aI(V), a2(V), and a3(V)
(1 1- 16), that are involved in the formation of a number
of molecular species (13,14,16), some of which are listed
in Table 1. The chains of Type V collagen likewise exhibit several distinct compositional features when compared to the interstitial collagen chains. Indeed, they resemble, but are readily distinguishable from, the
basement membrane collagen chains. It has been shown
Table 1. The genetically distinct types of collagen in connective tissue*
Types of collagen
Interstitial collagens
Type 1
Type I-trimer
Type 11
Type I11
[aI (1)12a2(I)
Basement membrane collagens
Type IVt
Pericelluar collagens
Type vs
a 1(V)a2(V)a3(V)
Large fibrils of dense connective tissue
Fibrillar form unknown
Small fibrils of hyaline cartilage
Fine reticular networks
Supporting elements in the morphologically distinct
basement membranes
Apparent supporting elements in basement membranelike exocytoskeletons
* This table includes only those collagens for which biochemical data are rather extensive. There undoubtedly exist other collagen types that remain to be localized (24) or biochemically characterized(25).
t The al(1V)-chain (3) has also been designated as C-chain (4-6), a”(1V)-chain (7), 140K (8) and PI
(9), and the a2(IV)-chain has also been called D-chain (4-6), cY’(1V)-chain (7), 70K (8) and P2 (9).
$The aI(V)-chain has also been designated as B-chain (1 l,l3,14) and aB (12,15), the a3(V)-chain has
also been called aC (15,16) and the a2(V)-chain has been termed A-chain (1 1,13,14) and aA (12,15).
that the Type V collagens are synthesized in significant
amounts by smooth muscle cells (17). In addition, immunohistochemical studies on a variety of cells and tissues have shown not only that the Type V collagens are
synthesized by a number of cell types, but that these
collagens appear to be deposited in large part peri cellularly when synthesized by smooth muscle cells (2,18),
striated muscle cells (19), fibroblasts (20), chondrocytes
(21), and the cells of embryonic blastocysts (22). Although the morphologic features of the Type V collagens as they exist in vivo are not currently known, it is
of interest that preparations of these collagens can be
induced to form cross-striated fibrils in vitro under conditions which are somewhat different from those used to
induce fiber formation on the part of the interstitial collagens (23).
With respect to rheumatology, it is of interest
that diarthrodial joints represent the major organ structures in which all of the currently well characterized
collagens contribute substantially to the formation and
maintenance of the connective tissues. We comment
herein on the localization of these collagens within the
joint structure as determined from both biochemical
and immunohistochemical studies and evaluate the significance of the more recent findings. In addition, we
note certain further studies and approaches in which the
information on the various collagens of the joint tissues
may be used in assessing the pathogenesis and progress
of joint disease.
Diarthrodial joints constitute the hinges of the
skeletal system. Due to its mineral content, bone repre-
sents the most physically stable connective tissue of the
joint. The intercellular bone matrix is comprised exclusively of collagen fibers containing Type I molecules
(26). The hyaline cartilage at the ends of bone provides
a smooth and somewhat elastic articulating surface.
About one-half of the hyaline cartilage extracellular
matrix is comprised of collagen fibers. The overwhelming majority of intercellular collagen matrix is
derived from Type I1 collagen molecules (26) which occur in fibers, exhibiting a great variation in size and
thickness (27). However, recent biochemical analyses
have shown that hyaline cartilage contains small
amounts of at least one form of Type V collagen, i.e.,
the [cy1(V)l3molecule (see Table 1) (13). Subsequent immunohistologic analyses have localized this particular
collagen pericellularly around the chondrocytes (2 1). It
is suggested, therefore, that this collagen forms part of
the chondrocyte microenvironment. The functions of
cellular microenvironments are undoubtedly quite complex and, as yet, little definitive information is available.
Nevertheless, it is possible that the structural elements
in these microenvironments serve to anchor or embed
the cells within their respective matrices. As far as
chondrocytes are concerned, therefore, the Type V collagen molecules locahzed pericellularly may function as
connecting elements between the cell surface and the interstitial fibrillar components derived from Type I1 collagen molecules. Of further interest in this regard are
the recent observations indicating that chondrocyte adhesion and the expression of the chondrocyte phenotype
is controlled, at least in part, by a specialized cartilage
Vascular smooth muscle
Vascular endothelium
Synovial stroma
Hyaline cartilage
Pericellular matrix
I,4, m ,m.p
Damaged cartilage
Figure 1. Collagen types in normal and rheumatoid joint.
glycoprotein designated chondronectin (28,29) by analogy with the fibroblast counterpart, fibronectin. Chondronectin may likewise be a constituent of the normal
chondrocyte microenvironment.
The mesenchyme-derived tissue which surrounds
the joint cavity in the form of a fibrillar condensed capsule is continuous with the dense connective tissue of
the periosteum and is comprised largely of tightly
packed fibers of high tensile strength derived from Type
I collagen molecules. The synovial membrane covering
the inner surface of the joint capsule lacks a continuous
basement membrane. However, the cells on the surface
of the synovial membrane are supported by a loose fibrillar network containing a mixture of fibers derived
from Type I and 111 collagen molecules (2). Due to the
presence of vessels within the synovial membrane, the
membrane likewise contains Type IV collagen derived
from the vascular endothelium, as well as Type V collagen associated with the pericytes and smooth muscle
cells of the vasculature (S Gay et al, unpublished results). These observations concerning tlie disposition of
the collagens in normal joint tissues are summarized in
diagrammatic form in the upper portion of Figure 1.
In certain diarthrodial joints, remnants of the accumulated intraarticular mesenchyme form fibrocartilaginous discs or menisci comprised predominantly of
dense fiber bundles derived from Type I collagen molecules (30).
In the inflammatory-proliferative phase, rheumatoid synovial tissue is characterized by the synthesis
and deposition of additional Type I and 111 collagens.
The blood vessels of the proliferating pannus tissue
carry the bulk of vascular-derived Type V collagen.
However, the endothelial basement membrane containing Type IV collagen often appears irregular, discontinuous, and sometimes multilamellated in the vessels of
pannus tissue. These observations are summarized in
diagrammatic form in the lower portion of Figure 1.
The altered basement membrane barrier is reflected by
the cellular synovial exudate. The exudate contains
phagocytes that exhibit inclusions of various collagens,
frequently associated with immunoglobulins and com-
plement components (3 1-33). The presence of different
collagens in phagocytes of the synovial fluid is apparently due to degradation and erosion of different parts
of the joint due to proteolytic activity on the part of collagenases (34). Phagocytosis of the vessel-derived collagens such as Type IV collagen from endothelium as well
as Type V collagen surrounding smooth muscle cells
and pericytes may reflect at least in part the degree of
vascular necrosis. The presence of Type I and I11 collagen within the exudate cells suggests the destruction of
the synovial matrix. However, the demonstration of
considerable amounts of Type I11 collagen may also reflect collagen neosynthesis as observed in fibroproliferative disorders (2). The existence of Type I1 collagen in
the synovial phagocytes undoubtedly indicates the erosion of articular cartilage. In this regard, initial biochemical investigations on the collagens in particles derived from synovial fluids have recently been performed
(35). However, immunologic procedures, such as immunofluorescence on synovial cells and radioimmunoassay
on synovial fluid using specific antibodies to the various
collagens may represent the most precise and sensitive
techniques in evaluating the nature and extent of initial
joint damage and the progress of the joint disease.
1. Miller EJ: Biochemical characteristics and biological significance of the genetically-distinct collagens. Mol Cell Biochem 13:165-192, 1976
2. Gay S, Miller EJ: Collagen in the Physiology and Pathology of Connective Tissue. Stuttgart-New York, Gustav
Fischer, Inc, 1978
3. Kefalides NA: Isolation of a collagen from basement
membranes containing three identical a-chains. Biochem
Biophys Res Commun 45:226-234, 1971
4. Gay S, Miller EJ: Characterization of lens capsule collagen: evidence for the presence of two unique chains in
molecules derived from major basement membrane structures. Arch Biochem Biophys 198:370-378, 1979
5. Dixit SN, Kang AN: Anterior lens capsule collagens: cyanogen bromide peptides of the C chain. Biochemistry
18:5686-5692, 1979
6. Kresina TF, Miller EJ: Isolation and characterization of
basement membrane collagen from human placental tissue: evidence for the presence of two genetically-distinct
collagen chains. Biochemistry 18:3089-3097, 1979
7. Glanville RW, Rauter A, Fietzek PP: Isolation and characterization of a native placental basement membrane
collagen and its component a chains. Eur J Biochem
95:383-389, 1979
8. Sage H, Woodbury RG, Bornstein P: Structural studies
on human Type IV collagen. J Biol Chem 254:9893-9900,
9. Timpl R, Bruckner P, Fietzek PP: Characterization of
pepsin fragments of basement membrane collagen obtained from a mouse tumor. Eur J Biochem 95:255-263,
10. Gay S, Kresina TF, Gay R, Miller EJ, Montes LF: Immunohistochemical demonstration of basement membrane
collagen in normal human skin and in psoriasis. J Cutan
Pathol6:91-95, 1979
11. Chung E, Rhodes RK, Miller EJ: Isolation of three collagenous components of probable basement membrane origin from several tissues. Biochem Biophys Res Commun
12. Burgeson RT, El Adli FA, Kailila 11, Hollister DW: Fetal
membrane collagens: identification of two new collagen
alpha chains. Proc Nat Acad Sci 73:2579-2583, 1976
13. Rhodes RK, Miller EJ: Physicochemical characterization
and molecular organization of the collagen A and B
chains. Biochemistry 17:3442-3448, 1978
14. Bentz H, Bachinger HP, Glanville R, Kuhn K Physical
evidence for the assembly of A and B chains of human
placental collagen in a single triple helix. Eur J Biochem
92~563-567, 1978
15. Brown RA, Shuttleworth A, Weiss JB: Three new achains of collagen from a non-basement membrane
source. Biochem Biophys Res Commun 80366-872, 1978
16. Sage H, Bornstein P: Characterization of a novel collagen
chain in human placenta and its relation to AB collagen.
Biochemistry 18:3815-3822, 1979
17. Mayne R, Vail MS, Miller EJ: Characterization of the
collagen chains synthesized by smooth muscle cells derived from rhesus monkey thoracic aorta. Biochemistry
1746-452, 1978
18. Miller EJ, Rhodes RK, Gay S, Kresina TF, Furuto DK:
Useful approaches in the isolation of the collagenous constituents of basement membranes, Frontiers in Matrix Biology. Vol. 7. Edited by L Robert. Basel, Karger, 1979, pp
19. Bailey AJ, Shellswell GB, Duance VC: Identification and
change of collagen types in differentiating myoblasts and
developing chick muscle. Nature 278:67-69, 1979
20. Gay R, Buckingham RB, Prince RK, Gay S, Rodnan GP,
Miller EJ: Collagen types synthesized in dermal fibroblast
cultures from patients with early progressive systemic
sclerosis. Arthritis Rheum 23: 190-196, 1980
21. Gay S, Rhodes RK, Gay R, Miller EJ: Collagen molecules comprised of the al(V)-chains (B chain): an apparent localization in the exocytoskeleton. Collagen Re1 Res,
in press
22. Sherman MI, Gay R, Gay S, Miller EJ: Association of
collagen with preimplantation and peri-implantation
mouse embryos. Dev Biol 74470478, 1980
23. Chiang TM, Mainardi CL, Seyer JM, Kang AH: Collagen-platelet interaction Type V (A-B) collagen induces
platelet aggregation. J Lab Clin Med 95:99-107, 1980
24. Furuto DK, Miller EJ: Isolation of a unique collagenous
fraction from limited pepsin digests of human placental
tissue. J Biol Chem 255:290-295, 1980
Burgeson RE, Hollister D W Collagen heterogeneity in
human cartilage: identification of several new collagen
chains. Biochem Biophys Res Commun 87:11241131,
Miller EJ: The collagens of joints, The Joints and Synovial Fluids. Vol. 1. Edited by L Sokoloff. New York-London, Academic Press, 1978, pp 205-242
Weiss C: Ultrastructural characteristics of osteoarthritis.
Fed Proc 32:1459-1466, 1973
Hewitt AT, Kleinman HK, Pennypacker JP, Martin GR.
Identification of an adhesion factor for chondrocytes.
Proc Nat Acad Sci 77:385-388, 1980
Kleinman HK, Hewitt AT, Murray JC, 'Liotta LA, Rennard SE, Pennypacker JP, McGoodwin EM, Martin GR,
Fishman PH: Cellular and metabolic specificity in the interaction of adhesion proteins with collagen and with
cells. J Supramol Struct 11:69-78, 1979
Eyre DR, Muir H: The distribution of different molecular
94 1
species of collagen in fibrous, elastic and hyaline cartilages of the pig. Biochem J 151595-602, I975
Mestecky J, Miller EJ, Gay S, Andriopoulos NA: Immune
response to collagen, Immunopathogenesis of Rheumatoid Arthritis. Edited by GS Panayi, PM Johnson. Surrey,
England, Reedbooks, 1979, pp 63-67.
Steffen C, Ludwig H, Kiiapp W: Collagen-anticollagen
immune complexes in rheumatoid arthritis synovial cells.
Z Immunitaetsforsch Immunobiol 147:229-237, 1974
Gay S, Remberger K: Rheumatoid arthritis: immunohistochemical studies with antibodies against collagen
type I, I1 and 111. Verh Dtsch Ges Pathol 60:29&291,
Hams ED Jr, Brinckerhoff CE, Vater CA: Release of collagenase from synovial tissues in rheumatoid arthritis, Immunopathogenesis of Rheumatoid Arthritis. Edited by
GS Panayi, PM Johnson. Surrey, England, Reedbooks,
1979, pp 147-153
Cheung HS, Ryan LM, Kozin F, McCarty DJ: Identification of collagen subtypes in synovial fluid sedimellts from
arthritic patients. Am J Med 68:73-79, 1980
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