45] Articular Cartilage and Osteoarthritis Joseph A. Buckwalter, MD Henry . Mankin, MD ‘Alan J. Grodzinsky, SeD Abstract Aniclar crag, which makes posible the painls, low-fiton movement of vil joins, ‘ons of sparsely dibs population of highly specialized el clled condita are cmbedded within a atx and provide ala carilee with remarkable mechanical properties, Crone tse atx macomelecdarframewar fom te ses of alee: cl- ages, protean, and noallageousprwins. The mati pres th els injury su ingfrom nol joint se, dete the pes ad concentrations of moles tht rch the els, cts 4 matic igual tansdcer for de ls, and helps wantin the coda phenotype ‘Throughout ie, aniuar cata nnderges internal remodeing as the cl repens macro roles lst though deadation, Aging decreases the abit of chondexyes to nina and retreat crag and thereby incases the rio degeneration ofthe ertcular cartilage sur ue Progesive degeneration of eicarcalge leads ont pain ond dynction tha is lin cally idenfed os osteoorts. Investigation regording the pathogenesis of postranmatic oscars, te form of ota ht develops flowing jo ini ping explain he development and pogesion of jon degeneration, Instr Course Lect 2005:54:65-480, ‘Synovial joints make normal, puinsree The tissue that conuibutes the most movement possible. These complex to these extraordinary functional cpaci- structures formed from maltiple distinct resis the articular carilage that forms the tissues including jointeapsule,Figaments, bearing surfaces ofall synovial joints ™* Te ‘menisci, subchondral bone, synovium, responds w alterations in us, and allows and hyaline articular cailage, have been pain-free movement with a level of fic- progressively refined over hundreds of sion less chan that of any prosthetic joint millions of years Walt Whitman recog- surface. Irvaies in thickness, cll density, nized the beauty ofthe design ofsymovial_ matrix composition, and mechanical joints when he observed that “the nar- properties within the same joint, among rowest hinge in my hand puts to scorn all _ joints, and among species Nonetheless, machinery. Despite the remarkable in all synovial joints it consists of the advances in joint arthroplasty, synovial same components, has the same general joins sill puto scom all machinery; no strueture, and performs the same fune- currently avaiable prosthesis comes close tions. Although 3t most omy 3 few mile to duplicating the function and durability limeters thick, it as surprising stifiness ‘of synovial joins to compression and resilience and excep- AAOS Instructional Course Lectures, Volume 54, 2005 ‘ional ability o distribute loads, thereby inimizing peak streses on subchondral bone." Perhaps most importantly, it has seat durablity—in many people it pro- vides normal joint function for 80 years or longer. Unforcunatly arcicular cartilage has 4 limited ability to maintain and repair itself and with age hese capacities decline. Asa result, the risk of progressive degeneration ofthe tse increases with time in individuals older chan 40 years* The degeneration of articular carlage and associated changes in subchondral nth joint pin and dysfnc- acterae oscoarthriis* For orthopaedic surgeons so under- stand how joint degeneration develops and progresses, it is important to be familiar with the current understanding of articular cartilage design (the ell and ‘mawix composition and structure that make posible che normal function of articular cartilage), che interactions benween chondrocytes and their marix that mainain the tisue, the biomechan- ies of the matrix, andthe issue degener- ation that leas to osteoarthritis Articular Cartilage Composition Upon gross and microscopic examina- tion, adul acl arlage appears tobe 2 smmpleineretsse, Opening normal synovial join exposes the smooth, sick. fina articular anlage sutics tha resist 465Basic Science Figure 1 Anicular cartilage fom the meal femoral condyle of an month-old rabbit, The ts sue is ganized int fut layers or zones: the sypericial zone (S), the vansiional zone the middie Vagal or deep) zone (M), and the cated eamiage zone (C). Bat = 50 nm (Reproduced fram Buckwalter JA, Hunziker EB, Rosenberg LC, eta: Aricularcatlage: Composition and seuctre, in Woo St, Bucwaler J eds: nur and Repair the AMusculoseltl Sot Tisues. atk Ridge, IL, American Academy of Orthopaedic Surgeons, 1988, pp 405-425.) deformation when probed. Light micro- scopic examination shows that articular cartilage consists primarily of extracella- lar matric with a sparse popaliion of cells and that it lacks blood vessls, Iym= phatic vesels, and nerves (Figures | and 2), Compared with tisues such as musele and bone, articular cartilage has a low level of metabolic activity; unlike these other tissues. its respouses to loading oF injury can only be detected by micros- copy or metabolic seudies, Despite iss ‘unimpressive appearance and low level of metabolic activiy study of the morphol- ‘ogy and biology of adult articular earti- lage shows that it hasan elaborate, highly ordered stricture and that complex inter- actions between the chondrocytes and the matrix maintain the tissue, Chondrocytes, Only one type of ell, the highly special- ized chondrocyte, exists within normal articular cartilage" (Figure 2). Chondro- cytes make up only about 1% of the vole 466 ‘ume of adult human atciculr eartilage (in other species, especially small animals seh as mice, rat, and rabbits with chin articular cartilages, the cell density is many times greater than in humans). Chondracytes from different cariage ‘ones differ in size, shape, and probably metabolic activity" but all ofthese cells contain the organelles necessary for mattix synthesis, including endoplasmic reticulum and Golg membranes. Also, they frequently conain intracytoplasmic filaments, lipid, glyco vesicles. Chondrocytes surround them selves with their extrac do not form cell-to-cell contacts, A spheroidal shape, synthesis of type I col- Tagen, large aggregating proteoglycans, and specific noncollagenous proteins dis- ‘inguish mature chondeoeytes from other cell Ax first glance, chondrocytes seem to be observers rather than partiipants in the function of mature articular cartilage They appear co remain unchanged in and secretory ular matrix and: size, location, appearance, and activity for decades. The unique mechanical proper tes of articular eatlage depend on the matrix (dhe types of macromolecules that form the famework of the mtv and the coneeniations of water and macro= molecules} However, amawix formed by mixing appropiate concentatons of water and eariage macromolecules (ol- lagens, proteoglycans, and. noncollage- sous protins) will not duplicate che properties of articular cattle. To pro- duce tissue that ean provide normal sj oval joint fnetion, the chondrocytes snus fst synthesize appropriate «ypes and amounts of macromolecules and then assemble and organize them into 3 highly ordered macromolecular fame work. Maintenance of the arseuar sur face requires tumover of the matrix macromolecules (continual replacement of degraded mtx components) and probably alteration in the matrix macro: molecular frameworkin response ojoint use. To accomplish these sci, the cells rust sense changes i the mate composition resulting fom the degrada- tion of macromolecules and the mechan- ical demands placed on ee articula su= face, and then respond by synthesizing appropiate sypes and amounts of maero= ‘molecules. Aging profoundly alters chondrocyte fanetion. With aging. the capacity of the cells syuesize some rypes of proteo- aiveans, cheir proliferative capacity and response t anaboli ttn includ tng growth factors decreases" These changes may limit the ably of to maintain and restore the Gssue and thereby contribute © the development and progression of articular cartilage degeneration Extracellular Matrix ‘The articular cartilage extracellular matrix consists of two components: ts sue fluid and the framework of struceural macromolecules that give the tissue its form and stability, The interaction of the AAOS Instructional Course Lectures, Volume 54, 2005Asticular Cartilage and Osteoarthritis tissue Muid and the macromolecular framework give the tissue its mechanical properties of sitfness and resilience “Tissue Fluid Water contributes up to 80% ofthe wer weight of articular cart- lage, andthe interaction of water with the matrix macromolecules. signiicantiy influences the mechanical properties of the tissue: This issue Avid contains 2s, small proteins, metabolites. and a high concentration of cations to balance the negatively charged proteoglycans. At least some ofthe water ean moxe Feely in and out ofthe tissue. Is volume, conce tration, and behavior within dhe tissue depends primarily on it interaction with the structural macromolecules, particu Tarly the large aggregating proteoglycans that help maintain the fluid within the matrix and fluid cleetolyte concentra tions. Because these macromolecules have a large number of negative charges that atzact positively charged fons and repel negatively charged. ions. they increase the concentration of positive fous such as sodium and decrease the concentration of negative ions suclt 25 clilorid. The increase in total inorganic jon concentration increases the tissue osmolarity (creating 2 Donnan effect). ‘The collagen network resists the Donnan osmotic pressure caused by the inorganic ions associated with the proceoglycans* Siructural Macromolecules The struc- tural macromolecules ofthe articular tilage (collagens. proteoglycans, and no collagenous proteins and glycoproteins) make up 20% t0 40% of its wet weight ‘The three classes of macromolecules df= fer in their concentrations within dhe articular cartilage and in thei contrib tions t0 its properties. Collagens con- tribute about 60% of the dry weight of anticular cartilage, proteoglycans. con- tribute 25% to 33%, and the noncollage- nous proteins and. glycoproteins con tribute 15% t0 20%, Collagens a distributed relatively uniformly through- ‘out the depth of the cartage,exeepe in the collagen-rich superficial zone. TI collagen fibilar meshwork gives care Tage its form and tensile strength.* Proteoglyeans and noncollagenous pro- ‘eins bind to the collagenous meshwork ‘or become mechanically entrapped with- in itand water fills this molecular frame- work. Some noncollagenous proteins help organize and stabilize the matrix macromolecular framework, whereas ‘others help chondrocytes bind to the macromolecules ofthe matrix. ‘ticular cartilage, like most tissues, ‘contains muliplegenetialydistines ele lagen types. specifically collagen types I VI, IX, X, and XL Collagen eypes I 1X. and XI form the cross-banded fibrils seen on electron microscopy (Figure 3). ‘The organization of these fibrils into a tight meshwork that extends chroughout the tissue provides the tensile stiffness and strength of anicular cartilage and contributes othe eohesiveness of thet sue by mechanically entrapping the large proteoglycans. Collagen rye Il accounts for 90% to 95% of the articular cartilage collagen and forms the primary compo- nent of the cross-banded fibrils. Type IX «collagen molecules bind covalently t the superficial layers of the cross-banded fibe rily and project into the matrix, where they also ean bind covalently to other type IX collagen molecules. Type XI col- lagen molecules bind covalently to type It collagen: molecules and probably form par of the interior structure ofthe cross- bonded fibrils. The functions of type IX and type XI collagens remain uncertain however, itis thoughe that they help form and stabilize the collagen fibrils assem bled primarily from eype Ul collagen. The projecting portions of type DX collagen molecules may also help bind together the collagen fibril meshwork and connect the collagen meshwork with prowogly- cans." Type VI collagen appears © form an important par of che matrix immeilatly surrounding the chondro- cytes and helps chondrocytes attach 0 the matric” The presence of type X collagen only near the cells of the calei- AAOS instructional Course Lectures, Volume 54, 2005, Chapter 45 Fire 2 Elecron micrographs showing the superficial zone (A). wansional zone (8), ridele raial or deep) zone (0, and cal fied cartilage one (D) of mature atcular cartilage chondrocyte rom the medial femoral condyle of a abit N = nucleus, G scone, IF = intermediate flamers, MM ‘mineralized matix, UN = unmineralized mati bar #3 nm. Reproduced from Buckwaller A, Hunziker €8, Rosenberg LC, cal: Artcular cartlage: Composition and structure, in Woo SL, Backwater J eds Injury and Repair of the Muscuosteleta Soft sues Park Ridge, IL, American Academy of ‘Onhopaedic Sugeons, 1988, pp 405-425) fed earilge zone of aricular earilage and the hypertophie zone of growth plate (where che longjcdinal carilage septa begin to mineralize) suggests chat it has role in cariage mineralization 467Basic Science Figure 3Elecron micrographs showing the superficial zone (A), tansional zone (8) "upper ponion ofthe mide racial or dep) zone (C), and lower portion ofthe middle zone (D) ofthe anicular cartilage imtenerior- {al max rom the mela emval condyle of an Bmorihold rabbit. Arrows indicate ro- teoglycans precipitated with thenium hexa- mine wichovide Ba = 0.5 nm. Reproduced from Buckwalter JA, Hunziker €, Rosenberg LC. et a Aricular cartilage Composition and structure, in Woo SL, Buckwale A eds: Injury and Repair ofthe Musculostlea Sit Tues Park Ridge, Il, American Academy of (Onhopaedic Sugeors, 1988, pp 405-425) Proceoglycans consist of a proxein core and one or more glycasaminogiycan chains (long unbranched polysaccharide 468 Figute 4 Transmission elecuon micrographs showing bovine antcuar cartilage proteoglycan aggregates from aca (A) and seer (8) consisting of cena hyaluronan flaments and multi- ple atiaced aggrecan. Aggregates ftom older animals have shorer hyaluronan lamers and fewer agarecas.n adstion, the aggrecans ae shoner and vary more in lergh. Bat = 500 am ‘Reproduced with permision from Buckwaler A, Kuetiner KE, Thonar ELM: Ageelated ‘changes in aicular cartilage proteoglycans: Election microscopic sudies, J Onhop Res 1985:3251-257) chains consisting of repeating disaccha- numbers of ehondeoitin sulfite and ker- rides that contain an amino sugar)" atan suite chains atached to a protein Each disaccharide unit has at least one core filament (Figure 5). Carilage also nngtively charged carboxylate or sulfite contains large nonaggreging proteogy= group so the glycosaminoglycans form cans that resemble aggrecans in structure long strings of negative charges chat and composition and may represent repel one another and other negatively degraded agrecans."™ DEcoRIn has one charged molecules and attract cations. dermatan sulfate chain, bigiyean has two Gilycosaminogiycans found in carlage dermatan sulfate chains, and fibromod- incu hyaluronic acid, chondroitin sul- ulin has several keratan sulfite chains fae, Keratan sullite, and dermatan sul- The eissue probably also contains other fare. The concentration of these mole- small proteoglycans that have not heen cules varies among sites within articular identified. Aggrecan molecules fill most cartilage and also with patient age, cart- of the interfibrillar space of the cartilage lage injury, and disease. matrix. They convibute about 90% of the Anticlar catlage contains evo major total cartilage matrix proteoglyean mass ferencation of phenorypicily dstinec populations of chondrocytes. Superficial Zone The unique se- cure and composition of the thinnest articular catage zone, the supertcal one, give it specialized mechanial and 470 possibly biologic properties. Ie eypically consist of wo layers. A sheet of fine fb- rils with litle polysaccharide and no eells covers the joint surfice. This portion of ‘the superficial zone presumably corre- sponds to the clear fil, often identified 2 the lamina splendens, which can be stripped from the antcular surice in some regions, Deep to this acellular sheet of fine fibis, flattened ellipsoid-shaped chondrocytes arrange themselves so that their major axes are parallel w the arti lar surface (Figure 2). They synhesize a ‘matrix that has high collagen concentea- tion and a low proteoglycan concentra~ tion celative co the other carilage zones, and examination of superficial zone cells in culture solution shows that they de- grade proteoglycans more rapidly. and synthesize less collagen and proteogly- cans chan cells from the deeper zones. Fibronectin and water concentrations are also highest inthis zon. ‘The dense mat of collagen fibrils Iying pale! to the joint surface in the superficial zone (Figure 3) helps deter- imine the mechanical properties ofthe ts- sue and affects the movement of mole- cues in and out of carte. Ie gives this cartilage zone greater tensile stiffness and strength than the deeper zones, and it may resist shear forces generated daring {inc use. In vitro experiments show that the superficial zone also makes an important contribusion to the compres- sive behavior of articular cartilage.” Removal ofthis zoneincreases issue pet- reabilty and probably inereases loading ‘of the macromolecular framework dut- ing compression; disruption or remodel- ing ofthe dense collagenous marx ofthe superficial zone is one of the fist detectable strctural changes in experi- mentally induced articular cartilage ‘degeneration, suggesting that alterations in this zone may contribute tothe devel- ‘opment of ostcoarthiis by altering che mechanical behavior of the vssue.® The densely packed collagen fibrils of the supertcial zone also ereate a “skin” for the articular cartilage that may lime ingress of lage molecules (uch as ani- bodies or other proteins) and che egress olage cartilage molecules. By sting asa barrier «9 postage of large molecules bercen che synovial Mid and the eaeti- Jag, the supericial zone may efecively isolte carige from the immune sys- tem. Thus, disruption of che superficial zone may noconly ale the steucere ad amechanial properties of anicular carti- lage, ie may also release catlage mole- cules that stimulae an immune of inflammatory response Transitional Zone As he name implies, the morphology and matrix com= position of the transitional zone is mediate between the superficial zone aid the midéle (radial or deep) zone. It usu ally has several fines the volume of the supeticial zone. The cells have a higher concentration of synthetic organelles, ‘endoplasmic reticulum, and Golg mem branes than superficial zone cells (Figure 2). Transional zone cells assume a spheroidal shape and synthesize a matric that has lager diameter collagen fibrils a higher proteoglycan concentation, but lower concentrations of water and cols gen than the superficial zone mati Middle Zone Tv chondrocytes inthe imide zone are spheroidal in shape. and they tend to align themselves in colurmas perpendicular to the joint surface {Figures 1 and2). This zone contains the Jaegst diameter collagen ibis the high est concentation of proeogyeans, and the lowest concentration of water. The collagen ibers ofthis zone pass int dhe tidemak, chin basophilic Tine seen on lige microscopic sections of deakfed articular cartilage that roughly cone- sponds to che boundary between calcified and unaleifed exage. The nature of the idernark resins uncerain.® Teamay result from concentration of basophilic caleiied marl ache imterfce between calcified and uncaleiied macs, possibly sccentated by the dase processing, and thus represent a “high water mark for ‘AAOS Instructional Course Lectures, Volume 54, 2005Asticular Cartilage and Osteoarthritis caicaion. One study ientied a band of fine fbi caespandng ta the tide mark, tematvelysogesing that rep resents a well-defined matrix structure.” Caled Cartilage Zone Asin zone of cad carige spares the middle zone (ucleiied eras) ad the b> honda! bove. The cel ofthe cleied tailage zone havea smal volume han the cells ofthe mide zone and conan nly small amount of endoplasmic rete tum and Gol membranes (Figure 2) Tn some regions, these cel appear co be compere surounded by cei cut Jag and buried in india ei sep- ulchers. This appearance suggests that they have an entermly low eve of meta telat. lower, ent works rst that they may havea tle in dhe development and progression of osteo ais” Matrix Regions ‘Variations in the matrix within zones dise tinguish three regions or compartments the pericellular macex, territorial matrix, and. interterritorial matrix (Figure 6) ‘The pericellular and cerrtorial regions appear ro serve the needs of chondrocytes by binding the cell membranes «0 the matrix macromolecules and_ protecting the cells fom damage during loading and deformation ofthe tissue. They may also help transmit mechanical signals the chondrocytes when the matrix deforms dating joine loading, The primary fanc- tion ofthe interteritorial matic (Figures 3 and 6) is to provide the mechanical properties of che issue Perielllar Matrix Chondrocyte cell membranes appear to attach tothe thin rim ofthe pericellular matrix that covers the cell surface (Figure 6). This mactix region is rich in. proteoglycans. and aso contains noncollagenous. matrix proteins, including the cell membrane associated molecule anchorin CUL8*and nonfibrillsr collagens, including type Vi collagen. Ie has ile or no fibril collagen. Territorial Matrix An envelope of ter- ritorial matrix surrounds the pericellular ‘matrix of individual chondrocytes and, in some locations, pais or clusters of chon- drocytes and their pericellular matrices (Figure 6). Inthe mide zone, a territor- ial matrix surrounds each chondrocyte column, The thin collagen fibrils of che territorial matrix nearest to the cell appear to adhere to the pericelular ‘matt. At a distance from the cel chey decussate and itersect at various angles forminga fibrilarbasket around te cells. This collagenous basket may provide mechanical protection for the chondro- ‘ytes during loading and deformation of the tissue. An abrupt increase in collagen fibril diameter and 2 tansition from the basketlike orientation of the collagen fibrils to a more panalel arrangement rmarks the boundary berween the terito- rial and interterrioral matrices. How- ver, many collagen fibrils connect the ‘oo regions, making it difficult «9 pre~ cisely identify the boundary beeween these region. Interteritoral Matrix The interterr- torial matrix makes up most of the vol= ‘ume of mature articular cartilage (Figures 1 and €). Te contains the largest diameter collagen fibrils. Unlike che collagen fib- ris of the territorial matrix, these fibrils are not organized to surround the chon-