Collagen is the most abundant protein in mammals and forms the main fibrous component of connective tissues like skin, bone and cartilage. There are many types of collagen that vary in structure and function. Collagen provides strength, support and elasticity to tissues. It is synthesized through a complex process involving post-translational modifications. Collagen in the periodontium includes types I, III, IV, V, VI and XII which provide structure and allow for adaptation to forces. The periodontal ligament has the most rapid collagen turnover of tissues in the body to enable response to occlusion forces.

1. COLLAGEN
Dr Gauri Kapila
MDS Ist year
Department of Periodontology and Oral
Implantology

2. CONTENTS
• Introduction
• Structure of collagen
• Types and functions of collagen
• Synthesis of collagen
• Collagen in periodontal tissue
• Degradation and remodelling of collagen
• Collagen disorders
• Biomedical applications
• Conclusion
• Refrences

3. INTRODUCTION
Intercellular substance-
homogeneous, nothing
more than a scaffold for
cells to grow or a medium
to “glue” cells together
Today, recognized as a
complex, interactive
compilation of
proteins in dynamic
equilibrium that can
regulate the gene
expression of cells

4. COMPONENTS OF EXTRACELLULAR
MATRIX
PROTEOGLYCANS
• (Mucoproteins) :
Conjugated proteins
• Protein +
Carbohydrate
• Carbohydrate part is
in the form of
Glycosaminoglycans
[GAGs].
• Versican
• Decorin
• Biglycan
• Syndecan
NON COLLAGENOUS
PROTEINS
• Elastin
• Fibronectin
• Laminin
• Osteocalcin
• Osteopontin
• Bone sialoprotein
• Osteonectin
• Tenascin
STRUCTURAL PROTEINS
• Collagen
• Elastin
• Keratin (epidermal
tissues)

5. COLLAGEN
• Most abundant protein in mammals -accounts for 25-30%
of their protein content.
• Main fibrous component of skin, bone, tendon and
cartilage.
• The word collagen comes from the Greek word, “kola,”
meaning, “glue producing”
• French word, collagene designates glue-producing
constraints

6. COLLAGEN
• When heated in water, it gradually breaks down to
produce soluble derived protein i.e. gelatin or animal
glue.
• Denaturates at a high temperature, remains stable at
body temperature.
• Miller and Matukas discovered collagen in 1969, since
then 26 new collagen types have been found.

7. COLLAGEN
• Collagen molecule (Tropocollagen)- rigid rod like
structure that resists stretching.
• Important structural component in tissues such as the
periodontal ligament, muscles and tendons in which the
mechanical forces need to be transmitted.
• Also influences cell shape, differentiation and other
cellular activities.
• An important group of multifunctional connective tissue
protein that participates in many biological functions.

8. BASIC STRUCTURE OF COLLAGEN
• 25 different genes coding for 14 different collagen
molecules.
• Prockop DJ, Kivirikko KI. Heritable diseases of collagen.
N Engl J Med 1984: 311: 376-386.
• 6 different collagen types detected in periodontium
• Uitto J, Murray LW, Blumberg B, Shamban A. Biochemistry
• of collagen diseases. Ann Intern Med 1986: 105:740-744

9. Types of collagen and respective
genes and tissues

10. BASIC STRUCTURE OF COLLAGEN
• Composed of 3 polypeptide alpha chains coiled
around each other to form the tripe helix
configuration- homotrimeric or heterotrimeric
•Depending on the type of collagen the molecule
may be made up of either 3 identical α chains or 2
or 3 different α chains.
(Ramachandran & Ramakrishnan 1976)

11. BASIC STRUCTURE OF COLLAGEN
• α chains- left handed helices that wrap
around each other into a right handed
rope like triple helical rod.
• Each such helix is around 1.4 nanometers
in diameter and 300 nanometers in length

12. BASIC STRUCTURE OF COLLAGEN
• 3 amino acids per turn.
• triple-helical sequences
comprising Gly-X-Y repeats, X
and Y being frequently (30%)
proline and 4-hydroxy-proline
• Glycine occupies every third
position in the repeating amino
acid sequence

13. BASIC STRUCTURE OF COLLAGEN
•Triple helix domain- separates globular domains within the
molecule- offers potential for lateral interactions from the X
& Y position
•The triple helix may be of a continuous stretch or it may be
interrupted by non collagenous elements.
•Glycine is essential for triple helical conformation because larger
amino acid will not fit in the center of the triple helical.
•Globular regions at the end of the molecules are important in
tissue processing and molecular stability.
•Collagen molecule is stabilized through the formation of a no. of
lysine derived intra & intermolecular cross links.

14. BASIC STRUCTURE OF COLLAGEN
• Molecular
formula:C2H5NOC5H9NOC5H10NO2.
• Hydrogen bonding takes place,
between the Oxygen and the
Hydrogen to form polymers from
monomers.
• Bonds between the different amino
acids- keeps them tightly together
in a ‘mesh of fibres’.
• Provides strength, which it gains
from the hydrogen bonds. Collagen fibres, with the main
amino acids.

15. TYPES OF COLLAGEN
• 19 types of collagens are
found
• Variations occur due to:
1. Differences in the assembly
of basic polypeptide chains
2. Different lengths of the helix
3. Various interruptions in the
helix and
4. Differences in the
terminations of the helical
domains

16. TYPES OF COLLAGEN (Perio 2000)
Fibrillar FACITs
Sheet forming Beaded filaments
Anchoring fibrils Growth plate specific
Miscellanous

17. Fibrillar collagens
Most commonly occurring collagen proteins
Greatest percentage of mass in all connective tissue
Formation of extensive linear aggregates
Exact parallel configuration of molecules
type I, type I trimer, type II type III type V type XI

18. Fibrillar collagens

19. FACITs (fibril associated collagens with
interrupted helices)
Does not form fibrils
Interrupted triple helices & large amino-terminal domains
Consist of 3 functional domains-
1. 1-2 helices interacts & adheres to fibrils
2. Projects out of the fibril
3. Non helical globular region
Connect fibrillar collagens to
the matrix
type IX, type XII, type XIV

20. FACITs (fibril associated collagens with
interrupted helices)

21. Sheet forming collagens
Non fibrillar collagens- helical & non helical domains
Like FACITs –unable to form compact banded fibers
type IV- complex branching net like structure whose
globular regions contact with other type IV molecules
type VIII- dumbell shaped- froms hexagonal lattices

22. Sheet forming collagens

23. Collagen forming beaded
filaments
Heterotrimeric molecule consisting of a short triple helix
domain with very large non helical amino and carboxyl
regions
Function of type VI not known
Accumulations seen in fibrotic and osteoarthiritic
disorders

24. Collagen forming beaded
filaments

25. Collagen forming anchoring fibrils
Homotrimeric molecule containing large globular region
Dimers associate in a linear non staggered fashion
Cell type responsible for secreting type VII- keratinocyte
Associates with type IV to secure basement membrane to
underlying stroma
Alterations seen in E. bullosa

26. Collagens forming anchoring fibrils

27. Growth plate specific collagens
Homotrimeric molecule-
type X-structural homology to type VIII but does not form
sheets
Secreted by hypertrophic chondrocytes
Associated with endochondral bone formation
Function not known
Influences remodeling of cartilage prior to calcification

28. Growth plate specific collagens

29. Miscellanous collagens
• type XIII
• no well defined function and stoichiometry
• α chains- 3 collagenous & 4 non collagenous
proteins

30. FUNCTIONS OF COLLAGEN
DIRECT FUNCTIONS
• provide matrix-specific cell attachment sites that can guide
migration, differentiation, and proliferation of a wide variety
of cells.
• interact directly with cells in at least three distinctive ways:
(1) via integrin receptors that recognize an Arg-Gly-Asp-Thr
sequence
(2) via adhesive proteins such as fibronectin and laminin
(3) via proteoglycans
• The effect of collagens on the differentiation of cells varies
with the collagen phenotype and the specific cell type.

31. FUNCTIONS OF COLLAGEN
• SUPPORTIVE ROLES
• imparts strength, support, shape and elasicity to the tissues.
• provides flexibility, support, and movement to cartilage.
• encases and protects delicate organs like kidneys and spleen.
• fills the sclera of the eye in crystalline form.
• Teeth(dentin) are made by adding mineral crystals to collagen.
• contributes to proper alignment of cells for cell proliferation
and differentiation.
• When exposed in damaged blood vessels, it initiates thrombus
formation.

32. BIOSYNTHESIS OF COLLAGEN
(Prockop & kivirikko 1995)
• Young tissue has high rate of collagen synthesis
• As the tissues matures in adults, synthesis continues as a
part of normal tissue turnover
• Highest rate of collagen turnover are observed in weight
bearing bones, lungs and periodontal tissues
• Collagen synthesis is elevated under conditions requiring
remodeling and replacement of tissues and during tissue
repair
• Elevated rates in pathological conditions such as fibrosis in
lungs and liver

33. Collagen sythesizing cells
• Synthesized by cells of mesodermal origin, collectively
referred to as fibroblast
• In highly differentiated state these fibroblast acquire
characters especially suited to the chemistry of the
tissues
• Chondroblast in cartilage
• Odontoblast in teeth
• Osteoblast in bone

34. BIOSYTNESIS OF COLLAGEN
• Collagen synthesizing cells
contains extensive RER and well
developed Golgi apparatus
• Synthesized in RER, passed into
Golgi and secreted into
extracellular space.

35. BIOSYNTHESIS OF COLLAGEN
TRANSLATION
Synthesis of
preprocollagen
(ribosomes)
Leader sequence of
AA directs to enter
lumen of ER
Cleaved into
procollagen (in the
lumen of ER)
POST
TRANSLATIONAL
MODIFICATIONS
Proline & lysine
undergo
hydroxylation &
glycosylation
Disulfide bonds
formed b/w 3
procollagen chains
twist to form triple
helix
REGISTRATION
Procollagen
molecule released
into the ECM from
golgi compartment
of ER
Aminoproteinase
and
carboxyproteinase
remove extra
terminal AA
Procollagen Collagen

36. BIOSYNTHESIS OF COLLAGEN
Removal of N and C terminal peptides

37. BIOSYNTHESIS OF COLLAGEN

38. Formation of collagen bundle

39. • Play major role in structure & function
• A set of intramolecular cross links joins the 3 α-chains
together
• These molecules are stabilized in fibers by an extensive
network in intermolecular cross links
• Decrease in cross links reduces the tensile strength of
collagen and contributes tissue fragility
Cross linking of collagen

40. Cross linking of collagen
• Most important cross links in collagen are derived
from specific lysine & hydroxylysine
• Intramolecular cross-links are formed by aldol
condensation of allysine residues
• Intermolecular cross-link formation involves
condensation between allysine or hydroxyallysine
residues with internal lysine or hydroxylysine residues
on adjacent molecules

41. Cross linking of collagen
• Number of cross-links is small in young, rapidly
growing animal, facilitates rapid turnover of collagen
necessary for the growth & remodeling process
• With increasing age, collagen becomes more and
more cross linked

42. Cross linking of collagen

43. Formation of collagen bundle

44. Mediators Major source Collagen synthesis
Growth factors
PDGF Platelets, macrophage,
smooth muscle cells, Epi.
TGF β Platelets, macrophage
FGF Platelets, macrophage
IGF Serum matrix
Cytokine/Lymphokine
IL-1 α,β Macrophages, most cells
INF-γ Lymphocytes
Hormones
Glucocorticoides
Others
PGE-2 Monocytes, macrophages
Mediators affecting collagen synthesis

45. COLLAGEN IN PERIODONTIUM
The periodontium is a unique organ
composed of 4 different tissue types that
vary in cellular composition, types and
amounts of proteins, mineralization,
degree of metabolic activity and disease
susceptibility.
1. Gingiva
2. Periodontal ligament
3. Cementum
4. Alveolar bone

46. COLLAGEN IN PERIODONTIUM

47. Gingival collagen
-In healthy gingiva, collagens account for approximately
three fifths of the total protein
-Major component- type I
-gingival type I & type III collagen has less proline &
hydroxyproline and considerably more lysine & hydroxylysine
than skin type I collagen
-gingival type V lacks hydroxyproline
-type IV & VI- unknown if biochemical composition differs from
the rest of the body

48. Gingival collagen
-metabolically active nature -continual
remodeling of the connective tissue in response
to various local and environmental
factors (such as the presence or absence of
teeth,inflammation, drugs, etc.)
-turnover of collagen -not as rapid as exhibited
in the periodontal ligament but is significantly
greater than found in other tissues such as skin,
tendon or palate.

49. Gingival collagen
-half life 8.5 days (transeptal fibers) 25 days
dentogingival fibers
-type I and type III collagen of edentulous area is
more similar to skin collagen- degree of
hydroxylation of lysine & proline
-lower conc of type V in edentulous areas
-the presence or absence of teeth -significant
changes in the biochemical character of the
gingiva.
-not yet known whether changes are involved in
or are a consequence of attachment loss around
teeth.

50. Gingival collagen
-other changes in gingival protein composition -inflammatory
processes.
-appearance of an additional collagen -shifts in the collagen ratios
-inflammation induced changes in the gingiva
-relatively small shift, approximately a 4% reduction, in type I
-type III -50% reduction
-type V -700% reduction (due to inc in blood vessels)
-appearance of type I trimer -2% of extractable collagen
Narayanan AS, Clagett JA, Page RC. Effect of inflammation on the distribution of collagen
types I, 111, IV, and V and type I trimer and fibronectin in human gingiva. 1 Dent Res 1985:
64: 1111-1116

51. Periodontal ligament collagen
-0.25 mm –cementum & alveolar bone
-the principal protein –collagen (dry
weight basis, 47% to 52% of protein).
-biochemical nature of the collagens
identified consists of collagen types I, III,
IV, V, VI & XII

52. Periodontal ligament collagen
-type I -80% (uniformly distributed) type II-second most
common (dispersed)
-function of type III –collagen turnover, tooth mobility and
collagen fibril diameter
-type IV -the basement membranes of the epithelial rests of
Malassez, blood vessels and nerves
-functions of V, VI & XII not known

53. Periodontal ligament collagen
-PDL -most metabolically active tissues in the body
-rapid turnover of proteins
-collagen metabolism -most of the protein activity in the PDL
-periodontal ligament incorporates proline at least 5 times
faster than gingiva or alveolar bone
-half-life -20% and 17% less than found in gingiva and alveolar
bone
metabolic activity of PDL -depends on location
-areas adjacent to the alveolar bone -rapid turnover
-half-lives differ between the apical and crestal regions

54. Periodontal ligament collagen
Biological significance of rapid metabolic turnover in the
periodontal ligament is not understood, but it may have
something to do with the adaptive function of this tissue
due to forces of occlusion, support, etc.

55. Cementum collagen
-comprised of thin (20- to 200-µm) mineralized organic matrix -
avascular, alymphic, non-innervated tissue -asymmetrically
populated by cells in lacunae
-50% -organic component –comprises of collagen
-type I -90%
-type III -5%

56. Alveolar bone collagen
-bone collagen -solely produced by osteoblasts -comprised
predominantly of type I collagen (85%), with small amounts of
type III and type V collagen (5%)

57. FUNCTIONAL ADAPTATIONS of
collagen
• Tooth support system is a multiphasic
system comprising of fibres , ground
substances, blood vessels, fluids acting
together to resist mechanical forces.
• Internal Orientation of collagen fibers
influences the mechanical properties of
the tissue . Collagen fibers best resist
axially directed force as majority of PDL
collagen fibers are arranged in to
Horizontal & Oblique direction.

58. FUNCTIONAL ADAPTATIONS of
collagen
• OVERLAPPING ARRANGEMENT of fibers as visible in
Electron Microscope looks like the spokes of a cycle
wheel.
• This is very crucial in withstanding Rotational & Intrusive
Forces.
• This overlapping arrangement helps in spreading the load
uniformly and reduce the strain on PDL.

59. Sharpey’s fibers
• The terminal ends of the
collagenous principal fibers are
inserted in to bones to form
Sharpey’s Fibers.
• These are enclosed within a
sheath of collagen Type III and
it not only confers elasticity on
the fibers but it also maintains
the elasticity of the fibers
when they are inserted in to
the bone by preventing their
mineralization.

60. Collagen crimping
• Collagenous tissues exhibit a quantifiable periodicity of
structure of variable scale, the waveform that describes
this periodicity has been referred to as crimp.
• In the polarizing microscope crimping can be seen by
regular banding of dark lines across the bundles.

61. Collagen crimping
• Causes-
• Sharp Zig-Zag arrangement of
collagen fibers with quantifiable
periodicity angular deflection
from axis
• Microanatomical organization of
collagenous sheets and bundles in
sinusoidal wave forms.

62. • Significance-
• It is an early ,easily extensible , non linear region that
causes the straightening out of the crimp, this enables
the ligament to absorb impact tensile loads without
extending collagen fibrils and without producing heat.
• Fibroblast processes in the developing collagenous
tissues play a role in fabricating the crimped
arrangement and consequently that crimping may be an
important feature in tooth eruption.
• It also has been proposed that crimp some times can
generate contractile forces in collagen molecules.

63. - breakdown of collagen -key component of normal
tissue remodeling
- pathways of degradation
• Intra cellular phagocytosis
• Extracellular MMPs
DEGRADATION OF COLLAGEN

64. • Recognition of the collagen fibrils to be
degraded
• Cleavage of the fibril
• Phagocytosis of the cleaved fibrils
• Formation of phagolysosomes
• Digestion of collagen fibers within the
phagolysosomes by lysosomal enzymes
(cathepsin)
INTRACELLULAR (Phagocytosis)

65. • Specialized enzymes that have evolved to specifically
to hydrolyze collagen
• Consist of atleast 24 members
• Contain Zn+2 at their active site & require Ca++ as
stabilizer.
• In general MMP’s are synthesized in a latent ,
nonactive form.
EXTRACELLULAR (MMP’s)

66. Specificities and source of collagenase &
other MMP’s

67. MMP’s of cells residing in periodontium
Cell type MMP inducers
fibroblast MMP-1 IL-1α,β; TNF-α
PDGFMMP-2
MMP-3
keratinocytes MMP-1
MMP-2
MMP-9
MMP-10
LPS, TGF-α
Monocytes,
endothelial
cells
MMP-1
MMP-2
MMP-9
MMP-3
PMN MMP-8
MMP-9
LPS

68. • Special collagenolytic enzymes may be released by some
infecting microorganisms
• Collagenase are produced by
Clostridium histolyticum
Pseudomonas aeruginosa
Mycobacterium tuberculosis
Some fungi
Collagenase produced by microorganism can cleave any
form of collagen into small peptide
Microbial collagenase

69. • MMP’s derived from PMNLs are believed to be
primarily responsible for tissue destruction
(overall et al1991)
• Whereas the enzymes synthesized by fibroblasts
and epithelial cells are believed to be involved in
normal tissue remodelling
(Sodek & overall 1992; Lee et al 1995)

70. • Highly specific group of enzymes that initiate & facilitate the
collagen degradation process
• Collagenase – an enzyme which cleaves the collagen
molecule in the helical portion at physiological PH &
temperature
• Its activity is prominent in periodontal tissues, where it is
elaborated by the gingiva, epithelial cells, CT cells and
alveolar bone
• Associated with orthodontic tooth movement, erupting tooth
germs & root resorption process
True collagenase

71. • Collagen is protected by several levels of controls on
collagenase action
• Controls range from synthesis & activation of collagenase to the
state of collagen itself
• Parathyroid hormone & hyperoxia- increases collagenase in
bone
• Corticosteroid- increases collagenase in cells & periodontium
• Prednisone, progesterone & cortisone- decreases collagenase
synthesis
Regulation of collagen degradation

72. • Chemical mediators of inflammation (PG & lymphokines) -
increases collagenase
• Complex formation with proteoglycans protects collagen
from collagenase
• Increase in cross-links in collagen - increases resistance to
collagenase
• Increased collagenase activity in rise of temperature, thus
higher in inflamed site

73. 1. Need of proenzyme activators for activation of MMPs 
plasmin, trypsin.
2. Modulation of its synthesis:
• Synthesis is induced by numerous mediators such as growth
factor, cytokines, or other similar mediator.
• Key regulators: IL-1, TGF-β present in abundance in inflamed
cells.
• TGF-β increases MMP’s synthesis in fibroblast but decrease in
keratinocytes.
Control of MMPs release

74. • In macrophages MMP production is stimulated by LPS & is
inhibited by IFN-γ, IL-4, IL-10
• Glucocorticoid & retinoid hormone also suppress MMP
production (Birkedal-Hansen et al 1993)
• Inhibition of collagenase activity by normal components of
serum- α2 macroglobulin which covalently cross-linked &
inactivate MMP’s
3. Existence of specific tissue inhibitors of MMPs activity
(TIMPs)

75. • TIMP secreted by the fibroblast & macrophages.
• Four members -TIMP-1, TIMP-2, TIMP-3, and TIMP-4.
• Acts by preventing the conversion of precursor forms of MMP’s
to active form.
• Forms irreversible complex with MMP’s via non-covalent
interactions (Welgus et al1985)
• TIMP-1 and TIMP-2 are capable of inhibiting the activities of
all known MMPs and as such play a key role in maintaining the
balance between extracellular matrix (ECM) deposition and
degradation in different physiological processes.
TIMP

76. • Chronic inflammatory periodontal disease (CIPD) clearly
involves the net destruction of collagen in extracellular
matrix.
• Pathology is related to a disturbance in the host
synthesis/degradation pathway.
• Low level, persistent bacterial infection  chronic
inflammation cytokine production induction of MMP’s
by host cells (Murphy 1993)
• Greater collagenase activity in presence of inflammatory
periodontal disease.
Collagen metabolism & periodontal disease

77. • Christner (1980) reported collagenase activity only in PDL’s
from teeth that had suffered loss of attachment.
• Level of tissue derived collagenase were also found to be
higher in GCF of CIPD patients compare to healthy control
(Larivee et al1986)
• Phagocytosis & intracellular lysosomal digestion play an
important role during normal collagen turnover (Wang et al
1982) & it is possible that this pathway is also be abnormal
during CIPD.
• Morris & Harper (1987) reported decreased amount of TIMP in
chronically inflamed periodontal tissue.

78. COLLAGEN DISORDERS (alterations in the
balance between anabolism & catabolism)
Collagen-related diseases arise from
genetic defects
nutritional deficiencies
They affect the biosynthesis, assembly, postranslational
modification, secretion, or other processes involved in normal
collagen production.

79. COLLAGEN DISORDERS
Ehler Danlos syndrome
Alport syndrome
Epidermolysis bullosa
Osteogenesis Imperfecta
Chondrodysplasias
Scurvy
Osteolathyrism

80. Properties of collagen (biomedical use)
Most useful biomaterial
• Weak immunogenicity
• Natural component of tissue hence tolerated
• Malleable
• Semi-permeable
• Possess haemostatic properties
• Supports cell proliferation is a lattice structure and cell
binding domain
• Facilitates early wound healing
• Chemotactic for fibroblasts
• Promotes cell migration
• Absorbed naturally

81. BIOMEDICAL APPLICATIONS
• Collagen membranes for GTR
• Drug delivery systems
• Collagen implants
• Matrix for Infuse BMP’s
• Cosmetic surgery
• Burns

82. LATEST ARTICLES

83. Conclusion
• The function of cells in the periodontium is the
culmination of numerous, intricate interactions
between cells and the substances that they secrete.
As our understanding of the periodontium evolves, we
must not only catalogue macromolecules but also
begin to define the nature of cell-matrix interactions
in the kaleidoscope of extracellular matrix domains.

84. Conclusion
• Collagens are fascinating proteins not only because they are
unique in structure and function, but also because of their
ubiquitous distribution throughout the animal kingdom.
• Collagen membranes have been used in both medical and
dental fields for decades. Collagen membranes have been
proven to significantly enhance periodontal regeneration in
various animal and human clinical trials however none of
these studies has shown a complete regeneration.
• A better understanding of the factors in the regeneration
process is required to achieve 100% predictable outcomes in
osseous defects around both teeth and implants.

85. REFERENCES
• The extracellular matrix of the periodontium: dynamic and
interactive tissues Periodontology 2000, Vol. 3, 1993, 39-63
• Periodontal ligament in health & disease; 2nd ed; Berkovitz
• Oral histology; 5th edition by Ten Cate
• Collagen family of proteins FASEB MICHEL VAN DER REST AND
ROBERT GARRONE

86. THANK YOU