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Cartilage

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Cartilage
Lightmicrographof undecalcifiedhyaline cartilageshowingchondrocytesandorganelles,lacunaeandmatrix.
Identifiers
MeSHD002356
TA98A02.0.00.005
TA2381
Anatomical terminology

Cartilageis a resilient and smooth type ofconnective tissue.Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane calledperichondrium.In tetrapods, it covers and protects theendsoflong bonesat thejointsasarticular cartilage,[1]and is a structural component of many body parts including therib cage,the neck and the bronchial tubes, and theintervertebral discs.In other taxa, such aschondrichthyansandcyclostomes,it constitutes a much greater proportion of the skeleton.[2]It is not as hard and rigid asbone,but it is much stiffer and much less flexible thanmuscle.The matrix of cartilage is made up ofglycosaminoglycans,proteoglycans,collagenfibers and, sometimes,elastin.It usually grows quicker than bone.

Because of its rigidity, cartilage often serves the purpose of holding tubes open in the body. Examples include the rings of the trachea, such as thecricoid cartilageandcarina.

Cartilage is composed of specialized cells calledchondrocytesthat produce a large amount of collagenousextracellular matrix,abundantground substancethat is rich in proteoglycan and elastin fibers. Cartilage is classified into three types —elastic cartilage,hyaline cartilage,andfibrocartilage— which differ in their relative amounts of collagen and proteoglycan.

As cartilage does not containbloodvessels ornerves,it is insensitive. However, some fibrocartilage such as themeniscusof thekneehas partial blood supply. Nutrition is supplied to the chondrocytes bydiffusion.The compression of the articular cartilage or flexion of the elastic cartilage generates fluid flow, which assists the diffusion of nutrients to the chondrocytes. Compared to other connective tissues, cartilage has a very slow turnover of its extracellular matrix and is documented to repair at only a very slow rate relative to other tissues.

There are three different types of cartilage: elastic (A), hyaline (B), and fibrous (C). In elastic cartilage, the cells are closer together creating less intercellular space. Elastic cartilage is found in the external ear flaps and in parts of the larynx. Hyaline cartilage has fewer cells than elastic cartilage; there is more intercellular space. Hyaline cartilage is found in the nose, ears, trachea, parts of the larynx, and smaller respiratory tubes. Fibrous cartilage has the fewest cells so it has the most intercellular space. Fibrous cartilage is found in the spine and the menisci.

Structure

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Development

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Main article:Chondrogenesis

Inembryogenesis,theskeletalsystem is derived from themesodermgerm layer. Chondrification (also known as chondrogenesis) is the process by which cartilage is formed from condensedmesenchymetissue, which differentiates intochondroblastsand begins secreting the molecules (aggrecanand collagen type II) that form the extracellular matrix. In all vertebrates, cartilage is the main skeletal tissue in early ontogenetic stages;[3][4]in osteichthyans, many cartilaginous elements subsequently ossify throughendochondraland perichondral ossification.[5]

Following the initial chondrification that occurs during embryogenesis, cartilage growth consists mostly of the maturing of immature cartilage to a more mature state. The division of cells within cartilage occurs very slowly, and thus growth in cartilage is usually not based on an increase in size or mass of the cartilage itself.[6]It has been identified that non-coding RNAs (e.g. miRNAs and long non-coding RNAs) as the most important epigenetic modulators can affect the chondrogenesis. This also justifies the non-coding RNAs' contribution in various cartilage-dependent pathological conditions such as arthritis, and so on.[7]

Articular cartilage

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Section from mouse joint showing cartilage (purple)

The articular cartilage function is dependent on the molecular composition of theextracellular matrix(ECM). The ECM consists mainly ofproteoglycanandcollagens.The main proteoglycan in cartilage is aggrecan, which, as its name suggests, forms large aggregates withhyaluronanand with itself.[8]These aggregates are negatively charged and hold water in the tissue. The collagen, mostly collagen type II, constrains the proteoglycans. The ECM responds to tensile and compressive forces that are experienced by the cartilage.[9]Cartilage growth thus refers to the matrix deposition, but can also refer to both the growth and remodeling of the extracellular matrix. Due to the great stress on the patellofemoral joint during resisted knee extension, the articular cartilage of the patella is among the thickest in the human body. The ECM of articular cartilage is classified into three regions: the pericellular matrix, the territorial matrix, and the interterritorial matrix.

Function

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Mechanical properties

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The mechanical properties of articular cartilage in load-bearing joints such as thekneeandhiphave been studied extensively at macro, micro, and nano-scales. These mechanical properties include the response of cartilage in frictional, compressive, shear and tensile loading. Cartilage is resilient and displaysviscoelasticproperties.[10]

Since cartilage has interstitial fluid that is free-moving, it makes the material difficult to test. One of the tests commonly used to overcome this obstacle is a confined compression test, which can be used in either a 'creep' or 'relaxation' mode.[11][12]In creep mode, the tissue displacement is measured as a function of time under a constant load, and in relaxation mode, the force is measured as a function of time under constant displacement. In creep mode, the tissue displacement is measured as a function of time under a constant load. During this mode, the deformation of the tissue has two main regions. In the first region, the displacement is rapid due to the initial flow of fluid out of the cartilage, and in the second region, the displacement slows down to an eventual constant equilibrium value. Under the commonly used loading conditions, the equilibrium displacement can take hours to reach.

In both the creep mode and the relaxation mode of a confined compression test, a disc of cartilage is placed in an impervious, fluid-filled container and covered with a porous plate that restricts the flow of interstitial fluid to the vertical direction. This test can be used to measure the aggregate modulus of cartilage, which is typically in the range of 0.5 to 0.9 MPa for articular cartilage,[11][12][13]and the Young’s Modulus, which is typically 0.45 to 0.80 MPa.[11][13]The aggregate modulus is “a measure of the stiffness of the tissue at equilibrium when all fluid flow has ceased”,[11]and Young’s modulus is a measure of how much a material strains (changes length) under a given stress.

The confined compression test can also be used to measure permeability, which is defined as the resistance to fluid flow through a material. Higher permeability allows for fluid to flow out of a material’s matrix more rapidly, while lower permeability leads to an initial rapid fluid flow and a slow decrease to equilibrium. Typically, the permeability of articular cartilage is in the range of 10^-15 to 10^-16 m^4/Ns.[11][12]However, permeability is sensitive to loading conditions and testing location. For example, permeability varies throughout articular cartilage and tends to be highest near the joint surface and lowest near the bone (or “deep zone” ). Permeability also decreases under increased loading of the tissue.

Indentation testing is an additional type of test commonly used to characterize cartilage.[11][14]Indentation testing involves using an indentor (usually <0.8 mm) to measure the displacement of the tissue under constant load. Similar to confined compression testing, it may take hours to reach equilibrium displacement. This method of testing can be used to measure the aggregate modulus, Poisson's ratio, and permeability of the tissue. Initially, there was a misconception that due to its predominantly water-based composition, cartilage had a Poisson's ratio of 0.5 and should be modeled as an incompressible material.[11]However, subsequent research has disproven this belief. The Poisson’s ratio of articular cartilage has been measured to be around 0.4 or lower in humans[11][14]and ranges from 0.46–0.5 in bovine subjects.[15]

The mechanical properties of articular cartilage are largely anisotropic, test-dependent, and can be age-dependent.[11]These properties also depend on collagen-proteoglycan interactions and therefore can increase/decrease depending on the total content of water, collagen, glycoproteins, etc. For example, increased glucosaminoglycan content leads to an increase in compressive stiffness, and increased water content leads to a lower aggregate modulus.

Tendon-bone interface

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In addition to its role in load-bearing joints, cartilage serves a crucial function as a gradient material between softer tissues and bone. Mechanical gradients are crucial for your body’s function, and for complex artificial structures including joint implants. Interfaces with mismatched material properties lead to areas of highstress concentrationwhich, over the millions of loading cycles experienced by human joins over a lifetime, would eventually lead to failure. For example, the elastic modulus of human bone is roughly 20 GPa while the softer regions of cartilage can be about 0.5 to 0.9 MPa.[16][17]When there is a smooth gradient of materials properties, however, stresses are distributed evenly across the interface, which puts less wear on each individual part.

The body solves this problem with stiffer, higher modulus layers near bone, with high concentrations of mineral deposits such as hydroxyapatite. Collagen fibers (which provide mechanical stiffness in cartilage) in this region are anchored directly to bones, reducing the possible deformation. Moving closer to soft tissue into the region known as the tidemark, the density ofchondrocytesincreases and collagen fibers are rearranged to optimize for stress dissipation and low friction. The outermost layer near the articular surface is known as the superficial zone, which primarily serves as a lubrication region. Here cartilage is characterized by a dense extracellular matrix and is rich in proteoglycans (which dispel and reabsorb water to soften impacts) and thin collagen oriented parallel to the joint surface which have excellent shear resistant properties.[18]

Osteoarthritis and natural aging both have negative effects on cartilage as a whole as well as the proper function of the materials gradient within. The earliest changes are often in the superficial zone, the softest and most lubricating part of the tissue. Degradation of this layer can put additional stresses on deeper layers which are not designed to support the same deformations. Another common effect of aging is increased crosslinking of collagen fibers. This leads to stiffer cartilage as a whole, which again can lead to early failure as stiffer tissue is more susceptible to fatigue based failure. Aging in calcified regions also generally leads to a larger number of mineral deposits, which has a similarly undesired stiffening effect.[19]Osteoarthritis has more extreme effects and can entirely wear down cartilage, causing direct bone-to-bone contact.[20]

Frictional properties

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Lubricin,aglycoproteinabundant in cartilage andsynovial fluid,plays a major role in bio-lubrication and wear protection of cartilage.[21]

Repair

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Cartilage has limited repair capabilities: Because chondrocytes are bound inlacunae,they cannot migrate to damaged areas. Therefore,cartilage damageis difficult to heal. Also, because hyaline cartilage does not have a blood supply, the deposition of new matrix is slow. Over the last years, surgeons and scientists have elaborated a series ofcartilage repair proceduresthat help to postpone the need for joint replacement. Atear of the meniscusof the knee cartilage can often be surgically trimmed to reduce problems.

Biological engineeringtechniques are being developed to generate new cartilage, using a cellular "scaffolding" material andcultured cellsto grow artificial cartilage.[22]Extensive researches have been conducted on freeze-thawedPVAhydrogelsas a base material for such a purpose.[23]These gels have exhibited great promises in terms of biocompatibility, wear resistance,shock absorption,frictioncoefficient,flexibility,and lubrication, and thus are considered superior to polyethylene-based cartilages. A two-year implantation of the PVA hydrogels as artificial meniscus in rabbits showed that the gels remain intact without degradation, fracture, or loss of properties.[23]

Clinical significance

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Human skeleton with articular cartilage shown in blue

Disease

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Main article:Chondropathy

Several diseases can affect cartilage.Chondrodystrophiesare a group of diseases, characterized by the disturbance of growth and subsequentossificationof cartilage. Some common diseases that affect the cartilage are listed below.

  • Osteoarthritis:Osteoarthritis is a disease of the whole joint, however, one of the most affected tissues is the articular cartilage. The cartilage covering bones (articular cartilage—a subset of hyaline cartilage) is thinned, eventually completely wearing away, resulting in a "bone against bone" within the joint, leading to reduced motion, and pain. Osteoarthritis affects the joints exposed to high stress and is therefore considered the result of "wear and tear" rather than a true disease. It is treated byarthroplasty,the replacement of the joint by a synthetic joint often made of a stainless steel alloy (cobaltchromoly) andultra-high-molecular-weight polyethylene.Chondroitin sulfateorglucosaminesulfate supplements, have been claimed to reduce the symptoms of osteoarthritis, but there is little good evidence to support this claim.[24]In osteoarthritis, increased expression of inflammatory cytokines and chemokines cause aberrant changes in differentiated chondrocytes function which leads to an excess of chondrocyte catabolic activity, mediated by factors including matrixmetalloproteinasesandaggrecanases.[25]
  • Traumatic rupture or detachment: The cartilage in the knee is frequently damaged but can be partially repaired throughknee cartilage replacement therapy.Often when athletes talk of damaged "cartilage" in their knee, they are referring to a damaged meniscus (afibrocartilagestructure) and not the articular cartilage.
  • Achondroplasia:Reduced proliferation of chondrocytes in the epiphyseal plate of long bones during infancy and childhood, resulting indwarfism.
  • Costochondritis:Inflammation of cartilage in the ribs, causingchest pain.
  • Spinal disc herniation:Asymmetrical compression of anintervertebral discruptures the sac-like disc, causing aherniationof its soft content. The hernia often compresses the adjacent nerves and causes back pain.
  • Relapsing polychondritis:a destruction, probablyautoimmune,of cartilage, especially of the nose and ears, causing disfiguration. Death occurs byasphyxiationas the larynx loses its rigidity and collapses.

Tumorsmade up of cartilage tissue, eitherbenignormalignant,can occur. They usually appear in bone, rarely in pre-existing cartilage. The benign tumors are calledchondroma,the malignant oneschondrosarcoma.Tumors arising from other tissues may also produce a cartilage-like matrix, the best-known beingpleomorphic adenomaof thesalivary glands.

The matrix of cartilage acts as a barrier, preventing the entry oflymphocytesor diffusion ofimmunoglobulins.This property allows for thetransplantationof cartilage from one individual to another without fear of tissue rejection.

Imaging

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Cartilage does not absorbX-raysunder normalin vivoconditions, but a dye can be injected into thesynovial membranethat will cause theX-raysto be absorbed by the dye. The resulting void on theradiographicfilm between the bone and meniscus represents the cartilage. Forin vitroX-rayscans, the outer soft tissue is most likely removed, so the cartilage and air boundary are enough to contrast the presence of cartilage due to therefractionof theX-ray.[26]

Histological image ofhyaline cartilagestained withhaematoxylin and eosin,under polarized light

Other animals

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Cartilaginous fish

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Cartilaginous fish (Chondrichthyes) orsharks,raysandchimaerashave a skeleton composed entirely of cartilage.

Invertebrate cartilage

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Cartilage tissue can also be found among some arthropods such ashorseshoe crabs,some mollusks such as marinesnailsandcephalopods,and some annelids like sabellid polychaetes.

Arthropods

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The most studied cartilage in arthropods is the branchial cartilage ofLimulus polyphemus.It is a vesicular cell-rich cartilage due to the large, spherical and vacuolated chondrocytes with no homologies in other arthropods. Other type of cartilage found inL. polyphemusis the endosternite cartilage, a fibrous-hyaline cartilage with chondrocytes of typical morphology in a fibrous component, much more fibrous than vertebrate hyaline cartilage, withmucopolysaccharidesimmunoreactive against chondroitin sulfate antibodies. There are homologous tissues to the endosternite cartilage in other arthropods.[27]The embryos ofLimulus polyphemusexpress ColA and hyaluronan in the gill cartilage and the endosternite, which indicates that these tissues are fibrillar-collagen-based cartilage. The endosternite cartilage forms close to Hh-expressing ventral nerve cords and expresses ColA and SoxE, a Sox9 analog. This is also seen in gill cartilage tissue.[28]

Mollusks

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In cephalopods, the models used for the studies of cartilage areOctopus vulgarisandSepia officinalis.The cephalopod cranial cartilage is the invertebrate cartilage that shows more resemblance to the vertebrate hyaline cartilage. The growth is thought to take place throughout the movement of cells from the periphery to the center. The chondrocytes present different morphologies related to their position in the tissue.[27] The embryos ofS. officinalisexpress ColAa, ColAb, and hyaluronan in the cranial cartilages and other regions of chondrogenesis. This implies that the cartilage is fibrillar-collagen-based. TheS. officinalisembryo expresses hh, whose presence causes ColAa and ColAb expression and is also able to maintain proliferating cells undiferentiated. It has been observed that this species presents the expression SoxD and SoxE, analogs of the vertebrate Sox5/6 and Sox9, in the developing cartilage. The cartilage growth pattern is the same as in vertebrate cartilage.[28]

In gastropods, the interest lies in theodontophore,a cartilaginous structure that supports the radula. The most studied species regarding this particular tissue isBusycotypus canaliculatus.The odontophore is a vesicular cell rich cartilage, consisting of vacuolated cells containing myoglobin, surrounded by a low amount of extra cellular matrix containing collagen. The odontophore contains muscle cells along with the chondrocytes in the case ofLymnaeaand other mollusks that graze vegetation.[27]

Sabellid polychaetes

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Thesabellid polychaetes,or feather duster worms, have cartilage tissue with cellular and matrix specialization supporting their tentacles. They present two distinct extracellular matrix regions. These regions are an acellular fibrous region with a high collagen content, called cartilage-like matrix, and collagen lacking a highly cellularized core, called osteoid-like matrix. The cartilage-like matrix surrounds the osteoid-like matrix. The amount of the acellular fibrous region is variable. The model organisms used in the study of cartilage in sabellid polychaetes arePotamillaspecies andMyxicola infundibulum.[27]

Plants and fungi

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Vascular plants,particularlyseeds,and the stems of some mushrooms, are sometimes called "cartilaginous", although they contain no cartilage.[29]

References

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Further reading

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