REVIEW ARTICLE

Collagen—The Skeleton of the Periodontium: A Review

Apoorva Sokke Mallikarjunappa1, Swati George2, Suchetha Aghanashini3, Divya Bhat4, Darshan B Mundinamane5,
Sapna Nadiger6

A b s t r ac t​
Aim and objective: The fibers of the periodontal ligament are a structurally integrated unit of fibrous components mainly collagenous in nature
and similar to the other supportive connective tissues. Collagen is the foremost abundant protein in mammals. Within the extracellular matrix,
they form supramolecular assemblies with a minimum of one triple-helical domain.
Background: The collagen family comprises 28 members. The fibers of the periodontium play a role in the structural organization of the tissues,
and contribute to its mechanical properties, by accommodating intensive forces from mastication and tooth eruption. They interact with cells
via several receptor families and regulate their proliferation, migration, and differentiation. Certain collagens have a restricted tissue distribution
and hence specific biological functions.
Review results: This review brings to light the synthesis, mineralization, and degradation of various types of collagen.
Conclusion: Collagen serves immense functions related to the structural integrity as well in the tooth-eruption mechanism. It presents with
a rapid turnover rate which along with its biochemical composition would thereby help in determining a pathological involvement causing
periodontal destruction.
Keywords: Biochemistry, Collagen, Crimping, Degradation, Mechanical support, Mineralization, Sharpey’s fibers.
Journal of Scientific Dentistry (2021): 10.5005/jp-journals-10083-0938

I n t r o d u c t i o n​ 1–6
Department of Periodontics, DAPMRV Dental College, Bengaluru,
The fibrous elements of the periodontium support it by providing Karnataka, India
tensile strength, whereas the ground substance dissipates the Corresponding Author: Swati George, Department of Periodontics,
compressional forces. These components, seen in the electron DAPMRV Dental College, Bengaluru, Karnataka, India, Phone: +91
microscope as an insoluble fibrillar network surrounded by a 9792174146, e-mail: swatigeorge@gmail.com
thixotropic gel, meet the functional requirements of tooth support How to cite this article: Mallikarjunappa AS, George S, Aghanashini S,
and eruption. Collagen is the most abundant and is often presumed Bhat D, Mundinamane DB, Nadiger S. Collagen—The Skeleton of the
to be the most important in terms of tooth support. Collagen is a Periodontium: A Review. J Sci Dent 2021;11(1):31–36.
protein composed of various amino acids; mainly glycine, proline, Source of support: Nil
hydroxylysine, and hydroxyproline. The collagen content in a tissue Conflict of interest: None
can be determined by its hydroxyproline content. The collagen is
formed by packing together of individual tropocollagen molecules
of approximately 5 μm in diameter and termed as principal fibers, The main types of collagen in the periodontal ligament are type I
with the bulk being type I collagen.1 and type III (Table 1).
C l a s s i f i c at i o n of C o l l ag e n T yp e s Type I Collagen
Olsen2 divided it into main groups Fibril collagen and FACIT It is the major protein component of most connective tissues. The
Collagens. biosynthesis and fibrillogenesis of type I collagen within PDL could
Fibril collagens include collagen type I, III, and V.2 be determined by studying its posttranslational modifications.8 It
FACIT collagens are fibrils-associated collagens with interrupted comprises two identical α1 chains and a α2 chain which is low in
triple helices, but it does not directly associate with the major band hydroxylysine and glycosylated hydroxylysine. Collagen type II is
collagen fibrils (Vonder Mark et al., 1984).3 a short-chain molecule that has only recently been located in the
According to Kielty and Grant,4 25 different gene sequences PDL (Romanos et al.)1,5
have been discovered encoding for collagenous polypeptides
giving rise to 13 distinct collagen types, which can be divided into Type III Collagen
three groups: The periodontal ligament is rich in type III collagen (about 20%)
The first, most abundant group is the fibrous collagens. These which is covalently linked to type I collagen relatively high in
are in the form of uninterrupted helices that are highly conservative hydroxyproline and cysteine whereas low in hydroxylysine. It is
and are mainly I, II, III, V, and XI. The second group is the high found in the periphery of Sharpey’s fiber attachments into the
molecular weight collagen, comprising of numerous intervening alveolar bone and around nerves and blood vessels, the function,
non-helical sequences, in association with the basement however, is unknown. A higher proportion of collagen type III is
membrane. Types IV and VII. The third group is a short-chain, non- present in fetal tissue (Berkowitz)5 and follows a similar distribution
helical domain, and consists of types VI, VIII, IX, X, XII, and XIII.5–7 pattern with the major fibrils throughout the tissue.

© The Author(s). 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://
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 Collagen—The Skeleton of the Periodontium: A Review

Table 1: Classification of collagen

Class Type Distribution
Fibril-forming (fibrillar) I Bone, skin, cornea, ligaments, tendon
II Cartilage, vitreous humor in the eye
III Skin, blood vessels
V Bone, dermis, co-distribution with type I
XI Cartilage, inverterbral discs, co-distribution with type II
XXIV Bone, cornea
XXVII Cartilage
Fibril-associated collagens with interrupted triple helices (FACIT) VII Bladder, dermis
IX Cartilage, cornea
XII Tendon, dermis
XIV Bone, dermis, cartilage
XVI Kidney, dermis
XIX Basement membrane
XX Cornea of chick
XXI Kidney, stomach
XXII Tissue junctions
XXVI Ovary, testis
Networking associated IV Basement membrane
VI Muscle, dermis, cornea, cartilage
VIII Brain, skin, kidney, heart
X Cartilage
XXVII Dermis, Sciatic nerve
Membrane-associated collagens with interrupted triple helices (MACIT) XIII Dermis, eyes, endothelial cells
XVII Hemidesmosomes in epithelia
XXIII Heart and retina
XXV Heart, testis brain
Multiple triple helix domains and interruptions (MULTIPLEXINs) XV Capillaries, testis, heart, kidney
XVIII Liver and basement membrane

Other Types of Collagen proline and y is often hydroxyproline) conferring its characteristic
Minute amounts of type IV, V, VI, and VII collagen have been found conformation.15–17
in the ligament. Type IV and VII collagen forms the major fraction
General Biosynthesis of Fibrous Collagens
of basal lamina protein of the blood vessels,9 the neurovascular
bundles and epithelial rests of PDL. It does not form fibrils and helps Fessler et al.18 found the precursor to be “procollagen” synthesized
maintain the structure and integrity of the PDL.10 from fibroblasts of tissue explants in vitro. Pro collagens possess
Type V is believed to be associated with the cell surface and a relative molecular mass greater than tropocollagen. They
coats the type III and type I fibrils. Type VI is a component of comprise peptide extensions on the C and N termini referred to as
oxytalan fibers though not directly associated with the major fibrils. propeptides. Cleavage of those propeptides may be a necessary
It may play a role in maintaining the integrity and elasticity of the prerequisite for fibrillogenesis within the ECM. Schofield and
extracellular matrix (ECM).11 Prockop19 at the pretranslational level.
Type XII collagen helps organize the ECM architecture of Synthesis of Procollagen
dense connective tissues12 and occurs only when the ligament
The ribosomes on the rough endoplasmic reticulum (RER)
is fully functional.12,13 This type has an NC3 domain that carries
initiates the biosynthesis of procollagen involving extensive
glycosaminoglycan chains, and it interacts with matrix proteins
cotranslation and posttranslational modifications controlled by
such as decorin, cartilage oligomeric matrix protein, fibromodulin,
various enzymes.20 Conversion from procollagen to collagen is a
and tenascin and could possibly be associated with the functional
specific process.21 Peltonen et al. proposed that the cleavage of
regeneration of the PDL14 (Table 2).
the carboxy-terminal propeptides of types I and III are differently
General Structure of Fibrous Collagens affected by lysine.22
All collagens are made up of three polypeptide chains organized Hydroxylation of Proline and Lysine
into a triple-helical structure15 with a mean diameter of 45–55 nm
Hydroxylation of PRO and LYS residues is a cotransitional
and transverse striations with a characteristic periodicity of 64 nm.
event occurring during chain elongation at the ribosome. 21 Its
Each polypeptide chain contains 1,056 amino acid residues, in the
cross-linking is based upon aldehyde formation from specific
form of the repeating tri-residue Motif (Gly-x-y), (where x is often
telopeptides, Knott and Bailey23 catalyzed by three hydroxylase

32 Journal of Scientific Dentistry, Volume 11 Issue 1 (January–June 2021)

 Collagen—The Skeleton of the Periodontium: A Review

Table 2: Ultrastructural distribution of collagen fibers

Tissue distribution Supramolecular organization Associations
Collagen type I Interstitium Cross-banded fibers; diameters Basic structural component associ-
≅ 30–35 nm; banding interval ≅ ated with collagen types III, V, VI, and
64 nm fibronectin
Collagen type III Interstitium Beaded fibers; diameter ≅ 15–20 Associated with other interstitial collagens
nm; beaded interval ≅ 40–64 nm and fibronectin
Collagen type V Interstitium Thin filaments ≅ 10 nm Associated with types I and III often
extending to this interstitial aspect of
vascular basement membranes
Collagen type VI Interstitium Thin filaments ≅ 10 nm Associated with types I and III often
extending to this interstitial aspect of
basement membranes
Fibronectin Interstitium and plasma Thin filaments and glomerular Associated with interstitial collagen
aggregates diameter ≅ 10 nm
Laminin Basement membranes both laminae but Not resolved Associated with type IV collagen
preferentially in the lamina rare
Collagen type IV Basement membrane both laminae but Not resolved Associated with laminin
preferentially in the lamina densa

enzymes which require Fe2+​, α-ketoglutarate, O2, and ascorbic Crimping can be recognized by a regular banding of dark
acid.19,20 This, however, ceases after triple-helix formation. lines across a collagenous bundle in polarizing microscopes,
The role of hydroxyproline and hydroxylysine in helix stability biomechanical studies, and X-ray diffraction analysis (Keller and
and cross-linkage is of prime importance and a failure results in Gathercole and Keller). 31,32 Crimping may either be due to the
a range of pathologies22 such as scurvy, and Menkes’ Kinky hair arrangement of collagen fibrils or due to the microanatomical
syndrome. The varied rates of PDL destruction amongst individuals organization of collagenous sheets and bundles (Gathercole and
speculate of distinctive lysine/hydroxylysine cross-linking variations Keller).31 SEM observations demonstrate the intertwining of fibrils
in collagen.23 with one another and in the outer region. 33 Birefringence studies
reported no evidence of fiber directional dispersions (Kolenda and
Glycosylation of Hydroxylysine and Asparagine Serwa et al., 2018).34
Glycosylation reactions are catalyzed by hydroxylysyl galac­
tosyltransferase and galactosyl hydroxylysyl glucosyltransferase Sharpey’s Fibers
and its amount varies with age and the type of tissue. Yamauchi Sharpey’s fibers (SF) are poorly mineralized fibers of the animal
and Sricholpech provided an overview on the enzymatic lysine tissue, composed mostly of several sorts of collagen, elastin, or
modifications and subsequent cross-linking to form covalent intra- tenascin35–37 embedded into the cementum and alveolar bone and
and inter-molecular cross-links.24 concentrated within the crestal region38,39 in various orientation. 37
Light microscopic observations suggest their continuity with
Helix Formation the periodontal ligament of adjacent teeth. On the premise of
Triple helix formation is initiated via the association of the three ultrastructural and microradiographic observations, Selvig 1965
C-terminal propeptides,25 whereas chain alignment begins by non- has reported that Sharpey’s fibers have unmineralized cores and are
covalent (hydrophobic) interactions at the C-terminal propeptide separated by lamellar bone fibers which are either randomly arranged
(Fessler et al.).18 The rate-determining step for helix formation is the or are parallel to the mineral surface.40 Immunohistochemistry
stabilization of the alignment by disulfide bonds in the propeptides reveals that Sharpey’s fibers are enclosed within a sheath of collagen
(Freedman)26 catalyzed by disulfide isomerase (Freedman and type III conferring elasticity and preventing remineralization.41
Hillson).27 Subsequently, the folding of the triple helix proceeds Scanning electron microscopy shows that the peripheral bone
rapidly. The procollagen molecule is then exported via the Golgi surrounding the Sharpey’s fibers may be mineralized to a level
apparatus in the classical secretory pathway, further processing slightly above or below the level of the bone surface and exhibit a
occurs by endopeptidases to form tropocollagen aggregates. The stippled appearance that indicates that the mineralization occurs
elimination of the propeptidases is achieved by enzymes belonging approximately at right angles to the axis of the fibers42 and this offers
to the class of matrix metalloproteinases.5 a mechanical advantage for transmitting axially directed forces and
tensional forces.43 The amount and ratio of collagenous protein in
Collagen Crimping the Sharpey’s fibers and adjacent alveolar bone, gets affected by
Collagenous tissues exhibit a quantifiable periodicity of the the intensity and characteristics of the orthodontic movements.44
structure of variable scale; ranging from submicroscopic to
anatomical; sinusoidal waveform. 28,29 This has been referred to Mineralization of Collagen
as “crimp” (Diamant et al., Gathercole).30,31 It was suggested that Collagen fibers are mineralized along their length and cores
the developing fibroblastic processes help fabricate the crimped with hydroxyapatite crystals. 45 A well-defined interface is
structure, thus a prerequisite in tooth eruption (Gathercole and present between the mineralized and non-mineralized collagen
Keller).31 within the PDL which implies a mechanism that retains the

Journal of Scientific Dentistry, Volume 11 Issue 1 (January–June 2021) 33

 Collagen—The Skeleton of the Periodontium: A Review

width (approximately 200 pm within the case of human PDL) of Table 3: Matrix metalloproteinases and collagen remodeling
unmineralized fibers. Sharpey’s fibers represent an embedding of Enzyme MMP Substrate Other substrates
the PDL fibers by entrapment in the advancing mineral front.40,46 Collagenases
Collagen mineralization may be mediated by restriction
Collagenase-1 MMP-1 I, II, III, VII, X Gelatin
enzymes such as alkaline phosphatase located in the bulk of the
(VIII, XI)
tissue adjacent to the alveolar bone. Several causes may lead to the
Collagenase-2 MMP-8 I, II, III (VII, VIII, Aggrecan and
failure of the mineralization of the PDL fibers. Cross linkage of PDL
X) gelatin
fibrils could lead to restriction of access of minerals to its nucleation
sites, thereby affecting the glycosylation of collagen, its assembly, Collagenase-3 MMP-13 I, II, III (IV, VI, X, Gelatin
XIV)
and the proteoglycans.5,34,47
Gelatinases
General Features of Collagen Degradation Gelatinase-A MMP-2 I, IV, V, VII, X (II, Gelatin
In the event of morphogenesis, the collagen undergoes breakdown III, X)
thus maintaining a balance between its degradation and synthesis. Gelatinase-A MMP-9 IV, V, XIV (XI) Gelatin
Collagen degradation is primarily associated with two Stromelysins
mechanisms: Stromelysin-1 MMP-3 III, IV, XI, X (II, Gelatin
• Various cells (fibroblasts, PMNs, and macrophages) in the healthy VII, XI)
or inflamed tissues secrete collagenases and other enzymes; Stromelysin-2 MMP-10 IV (III, V) Laminin,
(which degrade collagen and other matrix macromolecules into fibronectin, elastin
small peptides are called matrix metalloproteinases) destroy Stromelysin-3 MMP-11 IV Laminin,
collagen extracellularly. fibronectin,
• Secondly, fibroblasts degrade collagen fibers by phagocytosis. aggrecan
Cytoplasmic processes of the fibroblasts extend to the ligament– Matrilysins
cementum interface and thereby degrade the inserted collagen Matrilysin-1 MMP-7 IV (I) Laminin,
fibrils and the fibrils of the cementum matrix.1,5,6,7,48 fibronectin, gelatin

T h e co l l a g e n b r e a kd o w n i s m e d i a t e d via m a t r i x Matrilysin-2 MMP-26 IV Fibrinogen,

metalloproteinases—a group of zinc-containing endopeptidases fibronectin, gelatin
characterized by their metal-binding properties, and secreted
Membrane type MMPs
as inactive precursors, and inhibited by tissue inhibitor of
MT1-MMP MMP-14 I, II, III (and Laminin,
metalloproteinases (TIMP).
proMMP-2) fibronectin, gelatin
MMPs are predominantly secreted by fibroblasts and also
general (and
produced by some leukocytes (polymorphonuclear neutrophil proMMP-2)
leukocytes and macrophages). Six major matrix metalloproteases
MT2-MMP MMP-15 III Laminin,
are effective in collagen degradation. Matrix metalloproteinases are fibronectin, gelatin
also known to be inducible enzymes, and the cytokines, particularly
MT3-MMP MMP-16 Laminin,
interleukin-1, seem to play an important role in the control of their
fibronectin, gelatin
expression.49
MT4-MMP MMP-17 Fibrinogen, fibrin
The triple helix fibrillar collagen though resistant to proteolytic
degradation50 loses its conformation after cleavage, resulting MT5-MMP MMP-24 Laminin,
in a denatured molecule exposed to less specific proteases. The fibronectin, gelatin
regulation of MMP’s is important for the maintenance of tissue MT6-MMP MMP-25 IV Gelatin
morphostasis. The primary control is exerted by the production Others
of the inhibitor molecule.51 Tissue inhibitor of metalloproteinases  Macrophage MMP-12 I, IV Elastin, fibronectin
is a glycoprotein secreted by fibroblasts and macrophages. Tissue metalloelastase
inhibitor of metalloproteinases forms an irreversible complex with Enamelysin MMP-19 IV Aggrecan, elastin,
the MMPs via non-covalent interactions. TGFB also increases TIMP fibrillin, gelatin
production. XMMP MMP-20 Aggrecan
These can be further degraded by lysosomal enzymes (notably MMP-21 Aggrecan
cysteine proteases), which operate at acidic pHs. In contrast to the MMP-23 Gelatin, casein,
extracellular degradation of collagen, is an intracellular pathway fibronectin
of collagen phagocytosis and subsequent breakdown does not
CMMP MMP-27 Unknown Unknown
appear to involve matrix metalloproteinases.52–55 Glucocorticoids
Epilysin MMP-28 Unknown Unknown
and retinoids inhibit MMP production56–58 and simultaneously
increase the production of TIMP (Table 3).
albeit in much smaller amounts. Periodontal ligament collagen
is unusual in its supermolecular arrangement, rapid assimilation
C o n c lu s i o n​ into fibrils with an absence of non-reducible cross-links with age
The major fibrous protein of the PDL is type I collagen, with type and as compared with other soft connective tissues.59 This results
III collagen present in unusually high quantities (about 20% of in an extremely rapid rate of collagen turnover in the ligament.
collagen present). Types IV, V, VI, and XIl have also been detected, Collagen degradation is mediated by interstitial collagenase.

34 Journal of Scientific Dentistry, Volume 11 Issue 1 (January–June 2021)

 Collagen—The Skeleton of the Periodontium: A Review

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36 Journal of Scientific Dentistry, Volume 11 Issue 1 (January–June 2021)