normal posture 개선의 핵심 connective tissue의 6가지 종류와 특성

[문형철]

다음 질문.

예) cartilage : chondrocyte, ECM(GAGs+protein(collagen)+water), fibroblast

손상시 repair과정 속에서 각각 구성물들의 역할, ..

결합조직을 구성하고 있는 조직들과 특성

- 우리 몸에서 가장 많은 구성물인 결합조직, 총 에너지의 20%를 사용하는 거대한 조직, 단백질과 포도당, 물성분이 함께하여 gel like matrix, ECM의 주성분

6가지 종류

1) chondroitin sulfate

Chondroitin sulfate is an important structural component of cartilage and provides much of its resistance to compression.^[1] Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis.

Chondroitin sulfate is a major component of extracellular matrix, and is important in maintaining the structural integrity of the tissue. This function is typical of the large aggregating proteoglycans: aggrecan, versican,brevican, and neurocan, collectively termed the lecticans.

As part of aggrecan, chondroitin sulfate is a major component of cartilage. The tightly packed and highly charged sulfate groups of chondroitin sulfate generate electrostatic repulsion that provides much of the resistance of cartilage to compression. Loss of chondroitin sulfate from the cartilage is a major cause of osteoarthritis.

In several prospective controlled studies, chondroitin sulfate had been thought to decrease pain, improve functional disability, reduce NSAID or acetaminophen consumption, and provide good tolerability with an additional carry-over effect.^{[23][24][25][26][27][28][29]}

2) keratan sulfate

Keratan sulfate (KS), also called keratosulfate, is any of several sulfated glycosaminoglycans (structural carbohydrates) that have been found especially in the cornea, cartilage, and bone. It is also synthesized in the central nervous system where it participates both in development^[1] and in the glial scar formation following an injury.^[2] Keratan sulfates are large, highly hydrated molecules which in joints can act as a cushion to absorb mechanical shock.

3) dermatan sulfate

Dermatan sulfate is a glycosaminoglycan (formerly called a mucopolysaccharide) found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs. 

It is also referred to as chondroitin sulfate B, ^[1] although it is no longer classified as a form of chondroitin sulfate by most sources. Dermatan sulfate may have roles in coagulation, cardiovascular disease, carcinogenesis, infection, wound repair, and fibrosis.

Dermatan sulfate accumulates abnormally in several of the mucopolysaccharidosis disorders. An excess of Dermatan Sulfate in the Mitral Valve is characteristic of myxomatous degeneration of the leaflets leading to redundancy of valve tissue and ultimately, Mitral Valve Prolapse (into the Left atrium) and insufficiency. This chronic prolapse occurs mainly in women over the age of 60, and can predispose the patient to mitral annular calcification. Mitral valve insufficiency can lead to eccentric (volume dependent or dilated) hypertrophy and eventually Left Heart failure if untreated.

4) hyaluronic acid

Hyaluronan (also called hyaluronic acid or hyaluronate) is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. One of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors.

Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.^[7] For example, hyaluronan is a major component of the synovial fluid, and was found to increase the viscosity of the fluid. Along with lubricin(lubricating glycoprotein-1), it is one of the fluid's main lubricating components.

Hyaluronan is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of link protein, large highly negatively-charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.^[8]

Hyaluronan is also a major component of skin, where it is involved in tissue repair. When skin is exposed to excessive UVB rays, it becomes inflamed (sunburn) and thecells in the dermis stop producing as much hyaluronan, and increase the rate of its degradation. Hyaluronan degradation products also accumulate in the skin after UV exposure.^[9]

While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement and proliferation of cells, and participates in a number of cell surface receptor interactions, notably those including its primary receptors, CD44 and RHAMM. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes. Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in cell adhesion interactions required by tumor cells.

Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 (TLR2), TLR4 or both TLR2, and TLR4 in macrophages anddendritic cells. TLR and hyaluronan play a role in innate immunity.

High concentrations of hyaluronan in the brains of young rats, and reduced concentrations in the brains of adult rats suggest hyaluronan plays an important role in brain development.^[10]

Structure

Properties of hyaluronan were first determined in the 1930s in the laboratory of Karl Meyer.^[11]

Hyaluronan is a polymer of disaccharides, themselves composed of D-glucuronic acid and D-N-acetylglucosamine, linked via alternating β-1,4 and β-1,3 glycosidic bonds. Hyaluronan can be 25,000 disaccharide repeats in length. Polymers of hyaluronan can range in size from 5,000 to 20,000,000 Da in vivo. The average molecular weight in human synovial fluid is 3−4 million Da, and hyaluronan purified from human umbilical cord is 3,140,000 Da.^[12]

Hyaluronan is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.

Role of hyaluronan on wound repair process

Skin provides a mechanical barrier to the external environment and acts to prevent the ingress of infectious agents.^[24] Once injured, the tissues beneath are exposed to infection; therefore, rapid and effective healing is of crucial significance to reconstruct a barrier function. Skin wound healing is a complex process, and includes many interacting processes initiated by haemostasis and the release of platelet-derived factors.^[24] The following stages are inflammation, granulation tissue formation, reepithelization and remodeling. HA is likely to play a multifaceted role in mediation of these cellular and matrix events. The proposed roles of HA in this sequence of skin wound healing events are elucidated in details below.

Inflammation

Many biological factors, such as growth factors, cytokines, eicosanoids etc., are generated in the inflammation process. These factors are necessary for the subsequent steps of wound healing due to their roles in promoting migration of inflammatory cells, fibroblasts, and endothelial cells into the wound site.^[19]

The wound tissue in the early inflammatory phase of wound repair is abundant in HA, probably a reflection of increased synthesis.^[19] HA acts as a promoter of early inflammation, which is crucial in the whole skin wound-healing process. In a murine air pouch model of carrageenan/IL-1-induced inflammation, HA was observed to enhance cellular infiltration.^[19][25] Kobayashi and colleagues ^[19][26] showed a dose-dependent increase of the proinflammatory cytokines TNF-α and IL-8 production by human uterine fibroblasts at HA concentrations of 10μg/ml to 1 mg/ml via a CD44-mediated mechanism. Endothelial cells, in response to inflammatory cytokines such as TNF-α, and bacterial lipopolysaccharide, also synthesize HA, which has been shown to facilitate primary adhesion of cytokine-activated lymphocytes expressing the HA-binding variants of CD44 under laminar and static flow conditions.^[19][27] It is interesting to note that HA has contradictory dual functions in the inflammatory process. It not only can promote the inflammation, as stated above, but also can moderate the inflammatory response, which may contribute to the stabilization of granulation tissue matrix, as described in the following part.

Granulation and organization of the granulation tissue matrix

Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. It typically grows from the base of a wound and is able to fill wounds of almost any size it heals. HA is abundant in granulation tissue matrix. A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network. These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation and organization of the granulation tissue matrix.^[19] Absolutely, initiation of inflammation is extremely crucial for the formation of granulation tissue, therefore the pro-inflammatory role of HA as discussed above also contribute to this stage of wound healing.^[19]

HA and cell migration

Cell migration is essential for the formation of granulation tissue.^[19] The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for migration of cells into this temporary wound matrix. Contributions of HA to cell migration may attribute to its physicochemical properties as stated above, as well as its direct interactions with cells. For the former scenario, HA provides an open hydrated matrix that facilitates cell migration,^[19] whereas, in the latter scenario, directed migration and control of the cell locomotory mechanisms are mediated via the specific cell interaction between HA and cell surface HA receptors. As discussed before, the three principal cell surface receptors for HA are CD44, RHAMM, and ICAM-1. RHAMM is more related to cell migration. It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated protein kinase (ERK), p125fak, and pp60c-src.^[28][29][30] During fetal development, the migration path through which neural crest cells migrate is rich in HA.^[19] HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by HA degradation or blocking HA receptor occupancy.^[31]

By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration.^[32] Basically, HA is synthesized at the plasma membrane and released directly into the extracellular environment.^[19] This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.

Role of HA in moderation of the inflammatory response

Although inflammation is an integral part of granulation tissue formation, for normal tissue repair to proceed, inflammation needs to be moderated. The initial granulation tissue formed is highly inflammatory with a high rate of tissue turnover mediated by matrix degrading enzymes and reactive oxygen metabolites that are products of inflammatory cells.^[19] Stabilization of granulation tissue matrix can be achieved by moderating inflammation. HA functions as an important moderator in this moderation process, which contradicts its role in inflammatory stimulation, as described above. HA can protect against free-radical damage to cells.^[33] This may attribute to its free-radical scavenging property, a physicochemical characteristic shared by large polyionic polymers. In a rat model of free-radical scavenging property investigated by Foschi D. and colleagues, HA has been shown to reduce damage to the granulation tissue.^[34]

In addition to the free-radical scavenging role, HA may also function in the negative feedback loop of inflammatory activation through its specific biological interactions with the biological constituents of inflammation.^[19] TNF-α, an important cytokine generated in inflammation, stimulates the expression‎ of TSG-6 (TNF-stimulated gene 6) in fibroblasts and inflammatory cells. TSG-6, a HA-binding protein, also forms a stable complex with the serum proteinase inhibitor IαI (Inter-α-inhibitor) with a synergistic effect on the latter’s plasmin-inhibitory activity. Plasmin is involved in activation of the proteolytic cascade of matrix metalloproteinases and other proteinases leading to inflammatory tissue damage. Therefore, the action of TSG-6/ IαI complex, which may be additionally organized by binding to HA in the extracellular matrix, may serve as a potent negative feedback loop to moderate inflammation and stabilize the granulation tissue as healing progresses.^[19][35] In the murine air pouch model of carragenan/IL-1 (Interleukin-1β)-induced inflammation, where HA has been shown to have a proinflammatory property, reduction of inflammation can be achieved by administrating TSG-6, and the result is comparable with systemic dexamethasone treatment.

Reepithelization

HA plays an important role in the normal epidermis. HA also has crucial functions in the reepithelization process due to several of its properties. It serves as an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; its free-radical scavenging function and its role in keratinocyte proliferation and migration.^[19]

In normal skin, HA is found in relative high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found.^[36] CD44 is collocated with HA in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing the HA-rich matrix pouches.^[19][37] Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of HA in epidermis. Tammi R. and other colleagues ^[36] found HA content increases at the presence of retinoic acid (vitamin A). The proposed effects of retinoic acid against skin photo-damage and aging may be correlated, at least in part, with an increase of skin HA content, giving rise to increase of tissue hydration. It has been suggested the free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis.^[19]

Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair. In the wound healing process, HA is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression‎ in migrating keratinocytes.^[19][38] Kaya et al. found suppression of CD44 expression‎ by an epidermis-specificantisense transgene resulted in animals with defective HA accumulation in the superficial dermis, accompanied by distinct morphologic alterations of basal keratinocytes and defective keratinocyte proliferation in response to mitogen and growth factors. Decrease in skin elasticity, impaired local inflammatory response, and impaired tissue repair were also observed.^[19] Their observations are strongly supportive of the important roles HA and CD44 have in skin physiology and tissue repair.^[19]

Fetal wound healing and scarring

Lack of fibrous scarring is the primary feature of fetal wound healing. Even for longer periods, HA content in fetal wounds is still higher than that in adult wounds, which suggests that HA may, at least in part, reduce collagen deposition and therefore lead to reduced scarring.^[39] This suggestion is in agreement with the research of West et al., who showed in adult and late gestation fetal wound healing, removal of HA results in fibrotic scarring.^[19] Though the exact role of HA in skin scarring is still under investigation, based on all the facts that have been observed, it must be a great contributor to the less fibrous scarring.

5) heparin

heparan sulfate

1. chondroitin sulfate

- 인체에서 가장 많은 GAG

- Cartilage, tendons, ligaments, aorta에서 발견