of inflammation will actually inhibit repair and remodeling
and delay healing. The exact process of remodeling and repair
remains unclear and is undoubtedly more complex than described here. As new research is performed, the exact mechanisms mediating these responses may be discovered.
What is known is that fibroblasts are central to the connective tissue damage response. Also, proteoglycans support
repair as they supply the necessary glycosaminoglycans necessary to rejuvenate and create new collagen fibers. Going further, repair also involves the water transport systems as water
homeostasis between the extracellular matrix, cells and connective tissue must be achieved for proper tissue regeneration.
Because fibroblasts are the main cell type found in all kinds
of connective tissue and are involved in the regulation of
extracellular matrix protein production, in aged, diseased
or damaged connective tissue, fibroblast activity may be
reduced and unresponsive to epidermal growth factor, and
this may cause poor wound repair. 18 Studies have shown that
oxidative DNA damage contributes to replicative cessation in
human diploid fibroblast cells, but this process can be slowed
with the use of antioxidants and spin-trapping agents such
as alpha-phenyl-t-butyl nitrone (PBN), which can act like an
antioxidant. 19 Conversely, studies have also shown that fibroblasts use free radicals to stimulate proliferation, 20 but this
is a complex process involving a balance of precise mechanisms—a process just short of damage.
Fibroblasts are active players in adaptive immunity and
can transition acute inflammation to acquired immunity
through the cells’ ability to produce chemokines and the
extracellular matrix. In response to any damage or injury
that results in inflammation, the fibroblasts—which are
versatile connective tissue cells and can differentiate into
an array of other types of connective tissue cells including
cartilage, adipose tissue, bone and even circulate precursors
within blood—initiate an adaptive immunity response to
commence tissue repair. 21
Proteoglycans are the main component of the extracellular
matrix’s ground substance and are important in the regeneration and proliferation of collagen and, thus, connective
tissue. Proteoglycans are heavily glycosylated glycoproteins
or mucopolysaccharides and are also referred to as glycos-aminoglucans (GAGs). GAGs are predominantly made of
hyaluronate and sulfurs.
The building block for hyaluronic acid is glucosamine.
Studies have shown that the long-term use of glucosamine
sulfate can help repair tissue and reduce symptoms in os-
teoarthritis. 22 Literature also indicates that glucosamine
sulfate inhibits ICAM-1 production in conjunctival epithe-
lial cells in vitro. It is therefore plausible that future clini-
cal study may show that glucosamine sulfate functions well
to abate systemic inflammatory conditions caused by pro-
inflammatory cytokines. 23
Sulfur is found in every living cell in the body and it plays
a key role in collagen synthesis and immunity. 24 Early studies have also indicated that sulfur-containing foods like garlic,
onions, meat and cruciferous vegetables can offer anti-inflammatory and detoxifying benefits. The sulfur content in GAG
molecules allows them to possess a high negative charge density, so they repel each other and cause a space-filling function,
permitting them to store water and provide connective tissue
with cushioning compression strength and resiliency. 25
There are many kinds of collagen found within the body. They
consist of long chains of proteins derived from amino acids
and are found in the extracellular matrix. Collagen, together
with elastin, gives connective tissues great tensile strength.
Most kinds of collagen are either types I, II or III. Both the fibroblasts and epithelial cells make collagen. 26 Together with
GAGs and hyaluronic acid, the dermal matrix houses the collagen and elastin needed for a resilient epidermis. Collagen
and elastin consist of amino acids, which serve to protect connective tissues (blood vessels, nerves, tendons and ligaments,
and dermis). 27 Also protective, estrogen has been shown to
prevent a decrease in skin collagen in postmenopausal women, thus helping to maintain skin thickness. In addition, estrogen increases acid mucopolysaccharides and hyaluronic
acid in the skin, which suggests that it could play a role in
maintaining stratum corneum barrier function and connective tissue resilience. It has been postulated that estrogen
increases cutaneous wound healing because of its cytokine-regulating role. 28 In fact, topical estrogen has been found to
accelerate and improve wound healing in elderly men.
Also of note, essential fatty acids and antioxidants act
synergistically to moderate the induction of inflammatory
mediators, decrease free-radical tissue damage and inhibit
collagen and elastin breakdown from MMPs.
Cellular & Connective Tissue Water
Regardless of the precise mechanism of damage or location
of damage; e.g., fibroblasts, extracellular matrix, collagen,
the common pathway to deterioration in all tissues is water
loss. It has been suggested that if general cellular health is
addressed, simultaneous improvements in systemic, cutaneous and connective tissue health may be seen. This forms
the basis of The Water Principle theory, 29 and also the reasoning behind using a multidisciplinary strategy for connective tissue remodeling, repair and damage prevention.