The articular cartilage

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The articular cartilage of an adult human being is diverse in terms of structure and cellular organization, with both quantitative and qualitative variations in matrix constituents ranging from superficial to deep, between territorial and inter-territorial, as well as peri-cellular areas (Losina 2011, p. 220). Chondrocytes, the structural components of articular cartilage, retain the matrix structures. This happens under regular, low-turnover conditions, as glycosaminoglycans on proteoglycans and other non-collagen molecules are substituted. Another important matrix is the peri-cellular matrix that is made up of both quantitative and qualitative differences in the constituents of the matrix which range from superficial into the ones that are deep, between territorial and inter-territorial as well as regions that are peri-cellular (Losina 2011, p. 220). The matrix components are maintained by chondrocytes which are the cellular components of the articular cartilage. This occurs under conditions that are normal with low turnover where glycosaminoglycans present on proteoglycans and some non-collagen molecules get replaced. Another important matrix is the peri-cellular matrix that is made up of fibromodulin, collagen VI, matrilin 3 with very little or total absence of type II collagen.

Structure of the normal diarthrodial joint

These are types of joints that are freely moveable and therefore allow a lot of movements like in the knees, elbows and shoulders. These are in contrast with the amphi-arthrodial joints which only allow a slight form of movement (Fransen 2011, p.117). These diarthrosis joints are usually formed by the connection of bones with ligaments with a capsule separating them. A joint capsule fills the space between these joints using a synovial fluid which is lubricating in nature. These joints allow a lot of movements. The diathrotic joints offer little friction which is capable of withstanding a lot of wear and tear. These are the majority of joints in the body upon which a lot of movement occurs.

They can either be uni-axial, biaxial or multi-axial which are further divided in accordance to the movement they are engaged into. These include pivot, gliding, hinge, condyloid, ball and socket and saddle. The ends of bones in diathrosis joints are covered with a hyaline cartilage which is usually a thin layer. They lack cartilaginous tissue for connecting bones together (Goldring, Otero & Plumb 2011, p.215). This sets them into free movement. A joint capsule indirectly connects the bones covering and enclosing it. The joint capsule is made up of fibrous material and it encloses the joint cavity which is an inner surface lined with synovial material.

DiarthrosesJointImage by Madhero88 via Wikipedia

Major extracellular matrix components of the articular cartilage (aggrecan & collagen)

Articular cartilage forms one of the hyaline cartilage which is usually 2-40 mm thick. It’s devoid of blood vessels, nerves and lymphatic. Its extracellular matrix has sparse distribution of chondrocytes which are highly specialized. The main composition of the ECM includes collagen water and proteoglycans.


It is the most abundant macromolecule structure in the extracellular matrix and makes up 60% of the cartilage’s dry weight. Fibrils and fibres which are intertwined with aggregates of proteoglycan are as a result of type II collagen which is about 95% of the entire collagen. Other types of collagen ie I, IV, V, VI, IX and XI are also present but their contribution is minor (Chaudhari et al., 2008, p. 217). Their role is to form and stabilize the fibril network of type II collagen. The collagen types are at least 15 and made up of over 29 polypeptide chains. Members of collagen family contain a region which is made up of 3 polypeptide chains that are wound into triple like helix in nature. The polypeptide chain is made up of proline and glycine amino acids with stability being provided by hydroxyproline with the aid of hydrogen bonds present at the length of the molecule. The articular cartilage is provided with shear and tensile properties by the structure of the polypeptide chain which is triple helix. This assists in the stabilization of the matrix.


These are protein monomers that are heavily glycosylated. They are the second largest macromolecules in the extracellular matrix accounting for close to 15% wet weight. They are made up of a protein core plus linear glycosaminoglycan chains which are covalently attached. The chains have more than 100 monosaccharides and extend out from the core of the protein. They remain separated from each other due to charge repulsion. A number of proteoglycans make up the articular cartilage for normal functions such as decorin, aggrecan, fibromodulin and biglycan.

The aggrecan is the largest in size and abundant in weight. Its composed of chondroitin sulphate and keratin sulphate chains that are more than 100 in number. It has the ability to interact with hyaluronan where they form proteoglycan aggregates that are large in number using protein links (Greene, Banquy & Lee 2008, p.5256). The nterfibrillar space of the cartilage is occupied by aggrecan thus providing the cartilage with the osmotic properties that are used in the ability of the ECM to resist compressive loads.

Extracellular matrix of articular cartilage

Source: /images/

Changes that occur to the extracellular matrix which culminate in loss of integrity of the articular surface in osteoarthritis

In the process of osteoarthritis development, the chondrocytes which appear normal and quiescent get activated undergoing phenotypic shift thus resulting in the degradation and fibrillation of the matrix that makes up the cartilage, chodrocyte clusters also appears and calcification of the cartilage is experienced. This is associated with advancement of tidemark or even duplication followed by vascular penetration from the bone that is subchondral. The up regulation of the cartilage-degrading proteinases which occurs coincidentally leads to the production of products that degrade the matrix which further promote activation of catabolic activities, differentiation that is hypertrophy like, aberrant and eventual apoptosis (Fransen 2011, p.117). Upon degradation of the collagen network repair process to return it to the original state becomes impossible. The main therapeutic challenge therefore becomes promotion of repair or prevention of damage which should recapitulate the original functional and physiological properties of the cartilage.

Cartilage loss in osteoarthritis comes with many risk factors which in most cases have relations with the effects of trauma or organs overload on the normal cartilage or even normal loading which may occur on a cartilage that is already abnormal as a result of ageing or genetic defects. All these leads to biomechanics and alignment that is abnormal (Chang , Ramaswamy, & Serra 2012, p.159). An inflammatory component may exists and it’s marked by a joint pain, stiffness and swelling which gets accompanied with synovitis and release of inflammatory chemokines, cytokines and adipokines. All these are measurable in the synovial fluids of arthritic joints.

Inflammation in the arthritic cartilage

Once the stress and inflammation induced signalling are activated together with occurrence of posttranscriptional and transcriptional events release of chondrocytes takes place in the growth arrest, homeostasis that is imbalanced and activation of chondrocytes (Hembree et al., 2007, p.1390). All these are coupled with expression of inflammation related genes which are aberrant in addition to nitric oxide synthase-2, cyclooxygenase-2 and genes for catabolism like ADAMTS-4 and 5 and MMP-1,3 and 13. The kinases which are responsible for signalling are often activated by inflammatory stimuli and mechanical activities which include mitogen and stress activated ERK, p38, and JNK. These kinases activate AP-1. ETS, Runx2 as well as C/EBP factors for transcription (Lawrence 2008, p.31). The IKKα and IKKβ undergo activation respectively in the noncanonical (Re1A/p52) and canonical NF-κB (p65/p50) pathways (Ramakrishnan et al., 2010, p.918).

The secreted damage-associated molecular alarmins are some of the mediators used in the downstream activation of inflammatory and catabolic events in the articular cartilage and these include S100A4, A8, A9 and A11 including the high mobility group box protein 1and some ligands which operate through receptors that are toll-like for the glycan end products that are advanced. The RAGE ligands are known to increase the oxygen species that are reactive by the up regulation of the chemokines and cytokines (Mendel 2010, p.311). Such events end up causing oxidative stress and the apoptosis of chondrocyte through alteration of mitochondrial function. These ligands may also use the differential signalling pathways of NF-Κb leading to phenotypic shift of chondrocytes which causes expression of genes that are hypertrophy related like the Runx2 and COL10A1.

There are receptors for extramatrix components in the chondrocytes and most of these are responsible for catabolic activation and mechanical stimulation. They include inflammatory cytokines, integrins, fibronectin receptors, type II collagen fragments which are responsible for the stimulation and expression of proteinases (Loeser 2012, p.1698). All these serve as mechanisms for feedback stimulation once the degradation of matrix has been established.

Degradative enzymes responsible (metalloproteinases and TIMP) for osteoarthritis

The chondrocytes present in the articular cartilage synthesize many MMPs and cysteine proteinases and serine (Natoli & Athanasiou 2009, p.480). The enzyme activities are seen increasing in the OA by synthesis, activation of proenzymes by plasmin and other MMPs or even by decreased activities of the inhibitor for the effects of MMPs to be agonized, the levels of expression of inhibitors like the metalloproteinases (TIMP)-1 is in most cases reduced in OA with the ratios of total MMPs not being known. In many OA cases MMP-7 (matrilysin) enzyme which has many susceptible proteins becomes localized in chondrocytes and gets immunostained in the samples that are positive OA. The noncollagenase enzymes often act as disrupts to the matrix aking it weak and much vulnerable to hydration (Zhang & Jordan 2008, p.519).

The enzyme responsible for the degradation of many collllagen is MMP-13. MMP-3 is capable of cleaving the nonhelical telopeptide of types II and type IX collagens thus disrupting the cross-links in the collagen. Such cleavages in most cases lead to a fibril structure that is disrupted as well as the disruption of fibril function (Nielsen et al., 2008, p.80). When cartilage plugs are treated with stromelysin marked swelling of the tissues occurs but the use of trypsin does not lead to the same. There is therefore a presence of OA host of enzymes which is able to disrupt the network of collagens. Such disruptions often lead to joint destabilization any mutations that may occur in type II collagen is likely to cause unstable collagen networks and thus premature OA. The newest families of degenerative enzymes detected in articular cartilage include protein and mRNA FOR ADAM-10 (A Disintegrin-like and Metalloproteinae-like domain) found in fibrillated areas of OA cartilage more so in the cell clusters. Aggrecanase 1 and 2 are ADAMs enzymes with thrombospondin domains which bind to chondroitin sulphate (Michael 2010, p.158). Aggrecan are cleaved at distinct sites in the core protein by the MMPs and aggrecanases. Cathepsins present in OA cartilage and subcondral bone are found dominating zones that are undergoing remodelling and at inflammation sites. Any attempt to inhibit cysteine enzymes affects cartilage breakdown thus an indication that they take part in the events that lead to matrix degeneration (Losina 2011, p. 220).


Initiation and progression of cartilage damage are achieved by the common mediators in different osteoarthritis models which is observed in human form of the disease. Interaction among these mediators has been uncovered by many researchers in the past and has been seen to impact the process of this disease and thus informs medics about any new good directions for therapies.

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Chang CF, Ramaswamy G, & Serra R 2012, ‘Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis’, Osteoarthritis Cartilage, Vol. 20, no. 2, pp. 152–161

Chaudhari AM, Briant PL, Bevill SL, Koo S, & Andriacchi TP 2008, ‘Knee kinematics, cartilage morphology, and osteoarthritis after ACL injury’, Med Sci Sports Exerc, Vol.40, pp.215–222

Fransen M 2011, ‘The epidemiology of osteoarthritis in Asia’, Int J Rheum Dis, Vol.14, pp.113–121.

Greene GW, Banquy X, & Lee DW 2008, ‘Adaptive mechanically controlled lubrication mechanism found in articular joints’, Proc Natl Acad Sci U S A, Vol. 108, no. 13,pp.5255–5259.

Goldring MB, Otero M, & Plumb DA 2011, ‘Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis’, Eur Cell Mater, Vol. 21, pp.202–220

Hembree WC, Ward BD, Furman BD, Zura RD, Nichols LA, Guilak F, & Olson SA 2007, ‘Viability and apoptosis of human chondrocytes in osteochondral fragments following joint trauma’, J Bone Joint Surg Br, Vol.89, pp.1388–1395

Loeser RF, Goldring SR, Scanzello CR, & Goldring MB 2012, ‘Osteoarthritis: a disease of the joint as an organ’, Arthritis Rheum, Vol.64, pp. 1697–707

Losina E 2011, ‘Impact of obesity and knee osteoarthritis on morbidity in older Americans’, Ann Intern Med Vol. 154, pp. 217–226.

Lawrence RC 2008, ‘National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II’, Arthritis Rheum Vol. 58, pp.26–35.

Mendel OI 2010, ‘Osteoarthritis and vascular diseases in elderly patients: clinical and pathogenic interrelationships’, Adv Gerontol Vol.23 pp.304–313.

Michael JW 2010, ‘The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee’, Dtsch Arztebl Int, Vol.107, pp. 152–162.

Natoli RM, & Athanasiou KA 2009, ‘Traumatic loading of articular cartilage: Mechanical and biological responses and post-injury treatment’, Biorheology, Vol.46, pp.451–485

Nielsen RH, Stoop R, Leeming DJ, Stolina M, Qvist P, Christiansen C, & Karsdal MA 2008, ‘Evaluation of cartilage damage by measuring collagen degradation products in joint extracts in a traumatic model of osteoarthritis’, Biomarkers, Vol. 13, pp.79–87.

Ramakrishnan P, Hecht BA, Pedersen DR, Lavery MR, Maynard J, Buckwalter JA, & Martin JA 2010, ‘Oxidant conditioning protects cartilage from mechanically induced damage’, J Orthop Res. Vol.28, pp.914–920.

Zhang Y, & Jordan JM 2008, ‘ Epidemiology of osteoarthritis’, Rheum Dis Clin North Am, Vol. 34, pp. 515–529.

December 08, 2022

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