Connective Tissue Part 1: Tissue in Action
Author: Elzi Volk
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Athletes are mostly concerned with increasing strength
or speed in specific activities. Increasing muscle size and power,
endurance abilities, fuel utilization efficiency: these are often the
primary concerns in training. We spend much time, effort and money in
maximizing our muscle capabilities. However, an integral part of our
anatomy often takes a back seat: connective tissue.
Soreness from exercising is a familiar experience,
often an accepted incidental result of training. Most soreness results
from muscle tissue trauma, but stress is also induced upon the tissues
connected to the muscles: bones, tendons and ligaments. These tissues
are also subject to a manifestation of the second law of thermodynamics:
The human body is a magnificent piece of machinery
with rubber bands, hinges and joints throughout. Unlike the tin man, the
oilcan is not a option when our joints become ‘rusty’. When Humpty
Dumpty had his great fall, all the king’s army couldn’t put him back
together again. But if the tin man and poor Humpty had taken proper care
of their connective tissue, perhaps they would have healed and continued
squatting in their ripe old age.
I. What is connective tissue?
Aside from muscle tissue, connective tissue trauma is
a major source of physical discomfort, especially in athletes. This is
not surprising, considering that connective tissue is one of the most
abundant and widely distributed tissues in the body. It forms our bones,
surrounds our organs, holds our teeth in place, cushions and lubricates
our joints, and connects the muscles to our skeleton.
Connective tissue serves multiple functions. It
provides the organism with shape and mechanical support. Also, it
modulates cell migration, growth, and differentiation. The following are
major features of connective tissue:
Structural and mechanical: Connective
tissue supports the shape of cells, tissues, and organs interacting with
the cytoskeleton. The most obvious structural connective tissue is bone,
comprising the skeleton and supporting the entire organism.
Defense: It contains cells and metabolites
important in immune function, such as inflammation, and in tissue repair
Nutrition and transport of molecules: Blood
vessels, a connective tissue, transports substances throughout the body.
Components in connective tissue regulate movement of nutrients between
Storage: Adipose tissue is a unique connective
tissue, providing storage of energy and insulation.
Connective tissue function is mediated by its
different components, most of which are macromolecules that interact
with one another and with the cells. Varying the proportions and the
arrangement of the individual components determine the function of the
particular tissue. Several diseases are due to known defects in the
primary structure of one or more components. Disruptions in the
regulatory mechanisms of degradation contribute to conditions such as
osteoarthritis and complications in diabetes. As well, nutrient
deficiencies and various drugs may disrupt regulation of tissue
synthesis and degradation.
This article examines the influences of various
factors on the connective tissue types most affected by athletics:
cartilage, tendons, and ligaments. Information on the histology and
physiology of connective tissue is presented to enable readers to
understand how nutrition and various pharmaceuticals influence the
synthesis, degradation and remodeling of these tissues. Along with a
brief discussion of the effects of specific activities and metabolic
disorders, the roles of nutrition and several common drugs are examined.
II. Common characteristics (1,2)
Connective tissue is metabolically active and serves
many structural functions. The tissue consists of three basic
components: fibers, ground substance and cells. The fibers and ground
substance, which exist outside the cells, are collectively called the
extracellular matrix. The matrix separates and protects cells, bearing
weight, tension and offering defense. Mixed populations of cells with
various functions interact with the extracellular matrix contributing to
the various mechanisms in tissue physiology. Except for cartilage,
connective tissue is innervated (has a nerve supply). Vascularity (blood
supply) in tendons and ligaments is sparse, whereas cartilage is
avascular (has no blood supply). Further examination of the various
components will elucidate their contributions toward these attributes.
Fibers: Three major types of fibrous proteins
appear in connective tissue: collagen, elastic, and reticular fibers.
Tissues contain one or more types of collagen, and different proportions
of collagen and elastic fibers. Fibers associate with additional
components of the extracellular components and minerals to form
specialized connective tissue. The predominant fiber type usually
determines a tissue’s specific properties. Expression of connective
tissue types is largely a function of inherent cell types, external
environment, and physiological age of the organism.
Collagen is the most abundant protein, comprising of
~30% of total protein in the body. At least 14 types of collagen have
been isolated and characterized, and most tissues contain several types.
Collagen types may form fibrils or sheets, providing strength or
elasticity. All collagens share a common structure, varying in their
chemical composition, macromolecule organization, tissue distribution
and function. The most common collagen types are described in Table 1.
The other types are considered minor, though they are found in nearly
all tissues in tiny amounts.
Table 1. Major collagen types
and their characteristics.
|Skin, bone, tendon,
||Densely packed thick
resistance to tension
||Very thin fibers
|Skin, vessels, internal
organs, smooth muscle
||Loosely packed thin
||Thin amorphous sheets
||Support and filtration
Synthesis of collagen involves a cascade of
biochemical modifications of the original building blocks. Many enzymes,
cofactors and growth promoters influence these modifications which are
crucial to the structure and function of mature collagen. The most
abundant form of collagen, Type I, consists of three units of
polypeptide chains, which are comprised of subunits of amino acids.
Differences in the chemical structure of the polypeptide chains
determine the different collagen types. These chains intertwine in a
triple helix to form molecules called procollagen. Procollagen is formed
within the cell and subsequently transported outside of the cell into
the extracellular matrix. Outside the cell, procollagen is altered to
form tropocollagen, which is then able to form into microfibrils.
Microfibrils form fibrils when they are packed together in an
overlapping fashion. The microfibrils are held by hydrogen bonds,
hydrophobic interactions and reinforced by cross-links between
tropocollagen molecules. The characteristic types and amounts of their
cross-links largely determine the mechanical properties of collagen
fibers. As we shall see throughout this article, nutrient deficiencies
and pharmaceuticals may influence synthesis or metabolism during the
critical stages in development of collagen.
In collagen Type I and III, fibrils form fibers. These
fibers associate to form bundles in Type I collagen, but fibers are not
formed in Type II collagen (cartilage). The diameter of the fibers
depends on the number of fibrils they contain. Changes in fibril
diameter are often seen in aging and influenced by some pharmaceuticals
such as anabolic steroids.
Patterns between collagen types and orientation differ
between various connective tissues and even species. In general,
collagen fibers are inelastic, but have great tensile strength giving a
combination of flexibility and strength to the tissues they are in. The
diameter of the fibers and their orientation along the lines of stress
constitutes the tensile strength of a tissue.
Elastic fibers predominate in tissues subject to
stretching, such as ligaments, but are also found with collagen in
tendons, arteries, and skin. The length, thickness and distribution of
elastic fibers differ in the various tissues. Elastic fibers are
composed of elastin enclosed within tubular microfibrils, and are
thinner and tauter than collagen fibers. These fibers stretch easily, up
to one and one-half times their original length when the deforming force
is relaxed. Each elastin fiber forms a cross-linked network with other
elastin. The entire network can expand and contract like a rubber band.
Reticular fibers are extremely thin and branch to form
an extensive network in certain organs such as in smooth muscle, adipose
tissue, and bone marrow. These fibers consist of collagen protein
associated with glycoproteins and proteoglycans. During inflammation and
wound healing, most connective tissues have abundant reticular fibers,
which are subsequently replaced by regular collagen fibers.
Ground substance: The ground substance fills the
spaces in-between the cells and fibers. Its viscosity acts as a
lubricant due to the high water content. Soluble precursors of the
fibrous proteins, proteoglycans, glycoproteins and other molecules
secreted by cells are abundant in the ground substance.
The two major components of the ground substance are
the proteoglycans and structural glycoproteins, which trap water
molecules and lend strength, rigidity and resiliency to the
extracellular matrix. The chemical structure of proteoglycans determines
their size and structural function and are examined further.
Proteoglycans are large molecules formed by many
linear chains of polysaccharide units called glycosaminoglycans (GAGs).
Proteoglycan monomers are grouped according to the length and type of
GAG chains attached to a protein core. These GAG chains radiate out from
the core like bristles of a bottlebrush. Six classes of GAGs consist of
repeating modified two-sugar subunits. An amino sugar (glucosamine or
galactosamine) is always present as one of the two sugars in the
repeated subunits. These subunits are modified by the addition of
sulfate groups. As we will see, sulfation of the GAGs determines their
biological activity. Proteoglycan monomers may combine further with a
chain of hyaluronic acid, an unsulfated GAG, to form larger proteoglycan
complexes. As we shall see, these complexes, which may contain hundreds
of attached proteoglycan aggregates, constitute a significant role in
Proteoglycans act as a molecular sieve moderating the
movement of cells, and nutritive and inflammatory substances. The are
also responsible for attracting and maintaining water balance within the
tissue. The long chains of GAGs are negatively charged due to the
carboxylic (COO-) and sulfate (SO4-) groups of the amino
sugars. The high density of negative charges attracts and binds water
Depending on the structure and types of GAGs,
proteoglycans can trap as much as 50 times their weight in water. The
hyaluronic-proteoglycan aggregate molecules in cartilage resemble long
centipedes with hairy legs. The negatively charged GAGs
("hairs") repel each other and give the complex an open
structure, which occupies a lot of space. The highly polar 'hairs'
attract water molecules and the complex acts like a stiff sponge bounded
by the collagen network. When this 'sponge' is compressed, some of the
bound water is lost and therefore absorbs forces and redistributes them
equally. This is how cartilage protects structures in the joint from
mechanical (stress and weight) damage.
Glycoproteins are similar to proteoglycans. In
contrast, the protein fraction predominates over the carbohydrates,
which are branched structures. The primary glycoproteins are
fibronectin, laminin, and chondronectin. Their role in the ground
substance is the migration and adhesion of cells to their substrates.
For example, fibronectin connects fibroblasts to collagen and binds to
proteoglycans. These compounds contribute to the scaffolding in
connective tissue to provide support and influence movement of cells.
Cells: The various cells in connective tissue
store vital metabolites and synthesize fibrous proteins and other
components of the extracellular matrix. They play important roles in
immune and inflammatory responses as well as in tissue repair. Many
cells are indigenous to connective tissue. Some originate in bone
marrow, but are constantly present in the tissue. These resident cells
and their functions are listed in Table 2. Other cells migrate from
blood vessels in response to tissue injury, inflammation and repair.
They tend to disappear as healing progresses and inflammation subsides.
These cells include plasma cells, neutrophils, monocytes and basophils.
The discussion of inflammation will portray their role in tissue repair.
Table 2. Connective tissue
resident cell types and their functions.
||All connective tissues
||Structural fibers and
||GAGs and Type II collagen
||Collagen fibers and
||Originates in bone
marrow, present in all connective tissue
||Defense: phagocytosis of
foreign bodies and debris
||Originates in bone
marrow, present in all connective tissue
etc. immune function
Each class of tissues contains a fundamental cell type
that exists in mature and immature form. The active cells that
proliferate and secrete the ground substance and fibers are indicated by
the suffix -blast (meaning "forming"). The primary
blast cells are fibroblasts, chondroblasts and osteoblasts (see Table
2). Once the adult matrix is formed, the blast cells assume a less
active and mature mode and are indicated with the suffix -cyte
(meaning a cell). However, when the tissue is injured, cells can revert
to their more active mode to regenerate and repair the matrix
The rate of secretion of different substances by the
same cell varies with the age and hormonal influences of the organism.
Individual cells, such as the fibroblasts in connective tissue, rarely
divide into new cells unless the tissue requires additional cells as
when a tissue is damaged. During inflammation and repair, the numbers of
fibroblasts increase within some connective tissues. The extracellular
matrix greatly influences function and differentiation of the cells.
Tensile forces may also influence cell function, as changes in cell
shape may alter the responsiveness of the cell to hormones and growth
factors (3). The discussions on inflammation and pharmaceuticals examine
the influences of hormones and growth factors on cell function.
III. Physiology of connective tissue (2,4)
To understand how connective tissue is influenced by
activities, nutrition and pharmaceuticals, we must understand some basic
physiology of these tissues. Synthesis and degradation of tissues is a
continual process and are integral parts of tissue remodeling and
turnover. Many modulators can affect these processes, as we will see in
the ensuing discussion.
Each of the intracellular and extracellular events
involved in macromolecule synthesis is subject to alteration or
biochemical modification. Changes in gene transcription and in events
after translation of macromolecules can alter distribution and
deposition of tissue proteins and proteoglycans. For example, many
pathological conditions are attributable to abnormal or insufficient
collagen synthesis, such as scurvy and vitamin C deficiency.
Several modulators regulate synthesis and degradation
of connective tissue components: enzymes and cofactors, hormones and
growth factors, and cytokines. Because their roles are so complex,
examination of these specific regulators is beyond the scope of this
article. However, energy and nutritional status and various drugs
influence them and they will be discussed where relevant in the ensuing
Degradation of tissue components occurs during growth,
remodeling, inflammation, and repair of tissues. It can take place
during any point in synthesis of the various components. For example,
scurvy is a disease caused by deficiency of dietary vitamin C. Ascorbic
acid (vitamin C) is required in the enzymatic hydroxylation of the
prolyl and lysyl residues of collagen. Procollagen molecules lacking the
hydroxyproline residues have an unstable triple helix formation, are
susceptible to alteration and they are inadequately cross-linked.
Consequently, these molecules are then mechanically unstable and prone
to degradation. Therefore, the degree of degradation occurs at a much
greater rate than synthesis of collagen fibers. This is more pronounced
in area where collagen renewal tales place at a fast rate.
Specific enzymes initiate degradation of
macromolecules. Collagenases, which degrade collagen fibers, are
synthesized by various cell types and stimulated by hormones,
prostaglandins, and other substances secreted by lymphocytes and
macrophages. Metal ions, such as calcium, also regulate collagenase
activity. Enzymes within cellular lysosomes degrade proteoglycans. We
will see how synthesis and degradation are an integral part of tissue
Remodeling of tissues is the process of changing and
replacing tissue components with others. Normal remodeling during growth
or repair requires a proper balance of synthesis and degradation of
tissue components. Proteoglycans in the extracellular matrix appear to
regulate remodeling of connective tissue by influencing collagen
formation during the repair process. Remodeling is also regulated by
mechanical stimulation. Mechanical tension and compression modify bone
and cartilage remodeling, where tissues such as these depend on
diffusion of nutrients for maintenance since they have no direct blood
Turnover of connective tissue is the net balance
between synthesis and degradation of the macromolecules. A turnover
negative balance is characteristic of several inflammatory and joint
diseases where degradation occurs at a higher rate than synthesis. The
previous example of scurvy and ascorbic acid deficiency portrays the
significance of turnover balance of tissue components. The repair
process in tissue injury involves managing macromolecule turnover so
that synthesis equals degradation.
Turnover rate of various connective tissue components
varies. Elastin may take months to years for renewal. Collagen is also a
stable protein and renewal is slow. Replacement of mature collagen can
require weeks to several months. Collagen turnover rates vary in
different structures. Tendon collagen renewal is very slow, whereas the
collagen of loose connective tissue that surrounds our organs is renewed
Many alterations of connective tissue metabolism may
be due to changes in cross-linking in both collagen and elastin fibers.
Differences in amino acid composition of cross-links influence the
stability and turnover of these fibers. Although the same enzymes
process the collagen types and elastin during synthesis, the resultant
cross-links may be significantly different. Some types of cross-links
are more stable than others and therefore indirectly influence turnover
of fibers. For instance, 50-80% of collagens from tissues in bone and
cartilage is glycosylated and has a relatively higher turnover rate.
However, collagen fibers in tendons are not glycosylated and have a
lower turnover rate.
Proteoglycans turnover rapidly: 2-4 days for
hyaluronic acid and 7-10 days for the sulfated proteoglycans. In adult
humans, 250 mg of proteoglycans are catabolized in one day (5). The
polysaccharide chains of the proteoglycans are subject to modifications
similar to those of collagen
IV. Repair of connective tissue (2,6)
Injury to connective tissue involves damage to the
cells and structural components of the tissue. Several responses are
triggered and a sequence of events begins to repair the tissue. The
reaction to injury includes vascular, cellular and biochemical responses
which are outlined here.
Three phases of the repair process can be applied to
the general healing of connective tissue (7). These phases, however, may
overlap. These responses prevent the spread of damaging agents to nearby
tissues, dispose of damaged cells, and replace damaged tissue with newly
Acute inflammation phase: Immediately after
injury, several vascular and cellular reactions initiate the response
known as inflammation. The process begins with a release of chemical
mediators from cells into the extracellular fluid. The initial tissue
damage stimulates release of histamine from mast cells, which causes
dilation of blood vessels in the local area and increases vascular
permeability. Increased blood flow and fluids and proteins that leak
from the permeable blood vessels cause edema in the tissue and
consequent swelling. Cells migrate from nearby blood vessels and cause
release of more inflammatory mediators, such as kinins and
prostaglandins (PGs). Local tissue pressure and some of these mediators
act on nearby nerves to cause pain. These events lead to the classical
signs of inflammation: redness, swelling, pain and heat.
The primary purpose of inflammation is to rid the site
of damaged tissue cells and set the stage for tissue repair. Acute
inflammation generally lasts from 48 to 72 hours after an injury and
gradually subsides as the repair process progresses. Many of the events
that occur during this time initiate tissue repair. PGs are considered
important mediators of inflammation and are often the target of
intervention with anti-inflammatory agents. However, PGs may also have a
significant role in tissue repair. Many immigrant cells also have
significant roles in tissue remodeling. Leukocytes (white blood cells),
such as neutrophils and monocytes, accumulate within the damaged tissue
along with resident macrophages. Enzymes released from these cells help
digest necrotic cells and degrade matrix molecules; neutrophils and
macrophages engulf cell debris. Blood platelets release growth factors
that stimulate new fiber and matrix molecule synthesis.
Matrix and cellular proliferation phase: Chemical
mediators released by inflammatory cells stimulate migration and
proliferation of fibroblasts, which participate in the repair process.
Fibroblasts secrete fibronectin, proteoglycans and small diameter Type
III collagen fibers. In addition to these fibers, newly formed capillary
channels, clotting proteins, platelets and freshly synthesized matrix
molecules form granulation tissue. However, this granulation tissue has
little tensile strength.
Remodeling phase: Recall that remodeling reshapes
and strengthen damaged tissue by removing and reforming the matrix and
replacing cells. As repair progresses, inflammatory cells disappear, the
number of blood vessels and the density of fibroblasts decrease. The
proportion of Type I collagen to Type III collagen and the matrix
organization increases. Collagen fibers are reoriented in the direction
of loading, especially in ligament repair. Collagen matures and elastin
forms; tensile strength increases. However, the remodeled tissue may not
completely resemble the original and thus the mechanical capabilities of
that tissue may be altered.
Now that we have a background in connective tissue
biology, we will commence Part II with discussion of specific connective
tissues and some of their pathophysiology. We will also examine the
roles of nutrition and several pharmaceuticals in tissue healing and
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