Available online http://arthritis-research.

com/content/3/2/107

Review
Articular cartilage and changes in arthritis
An introduction: Cell biology of osteoarthritis

commentary
Linda J Sandell* and Thomas Aigner†

*Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, USA
†Cartilage Research – Department of Pathology, University of Erlangen-Nurnberg, Erlangen, Germany

Correspondence: Linda J Sandell, PhD, Washington University School of Medicine, Department of Orthopaedic Surgery, Mail Stop 90-34-673,
216 South Kingshighway, St Louis, MO 63110, USA. Tel: +1 314 454 7800; fax: +1 314 454 5900; e-mail: [email protected]

Received: 14 November 2000 Arthritis Res 2001, 3:107–113

Revisions requested: 29 November 2000 This article may contain supplementary data which can only be found

review
Revisions received: 12 December 2000 online at http://arthritis-research.com/content/3/2/107
Accepted: 15 December 2000 © 2001 BioMed Central Ltd
Published: 22 January 2001 (Print ISSN 1465-9905; Online ISSN 1465-9913)

Abstract
The reaction patterns of chondrocytes in osteoarthritis can be summarized in five categories:
(1) proliferation and cell death (apoptosis); changes in (2) synthetic activity and (3) degradation;
(4) phenotypic modulation of the articular chondrocytes; and (5) formation of osteophytes. In
osteoarthritis, the primary responses are reinitiation of synthesis of cartilage macromolecules, the

reports
initiation of synthesis of types IIA and III procollagens as markers of a more primitive phenotype, and
synthesis of active proteolytic enzymes. Reversion to a fibroblast-like phenotype, known as
‘dedifferentiation’, does not appear to be an important component. Proliferation plays a role in forming
characteristic chondrocyte clusters near the surface, while apoptosis probably occurs primarily in the
calcified cartilage.

Keywords: cartilage, cell biology, chondrocyte phenotype, osteoarthritis

Introduction perpetuation of OA. Analysis of mRNA levels in cartilage

primary research
Osteoarthritis (OA) involves the entire synovial joint, chondrocytes remaining even at joint replacement pro-
encompassing the cartilage, synovium, and underlying vided a surprise: the cells are not metabolically inert, but
bone. The cells in each of these tissues have indepen- are actively synthesizing cartilage proteins. The proteins
dent capacities to initiate and respond to injury in the synthesized by OA chondrocytes are structural and func-
joint, ultimately resulting in degeneration of cartilage. It is tional macromolecules, and degradative enzymes. In
generally believed that degeneration of cartilage in OA is addition, the areas of cellular activity and inactivity are
characterized by two phases: a biosynthetic phase, now known to be regional. Unfortunately, at some point
during which the cells resident in cartilage, the chondro- the biosynthetic anabolic activity is unable to keep pace
cytes, attempt to repair the damaged extracellular matrix; with the degradative catabolic activity, and degeneration
and a degradative phase, in which the activity of of the tissue results.
enzymes produced by the chondrocytes digests the
meeting abstracts

matrix, matrix synthesis is inhibited, and the consequent Influences of cytokines and growth factors
erosion of the cartilage is accelerated [1–4]. New tech- In normal adult cartilage, chondrocytes synthesize matrix
niques of molecular biology have provided invaluable components very slowly. During development, however,
insights into the function of cells during the onset and biosynthesis is stimulated by a variety of anabolic

BMP = bone morphogenetic protein; COL2A = type IIA procollagen; COL2B = type IIB procollagen; FGF = fibroblast growth factor; IGF = insulin-
like growth factor; IL = interleukin; MMP = matrix metalloproteinase; NO = nitric oxide; NOS = nitric oxide synthase; OA = osteoarthritis; TGF =
transforming growth factor; TIMP = tissue inhibitor of metalloproteinases; TNF = tumor necrosis factor.
Arthritis Research Vol 3 No 2 Sandell and Aigner

cytokines and growth factors, such as transforming Cellular responses in OA cartilage

growth factor (TGF)-β, bone morphogenetic proteins The cellular reaction pattern during the osteoarthritic
(BMPs), and insulin-like growth factor I (IGF-I). In OA, disease process is at first glance rather heterogeneous.
many of these factors – and others, such as the inflamma- However, the reaction patterns can basically be summa-
tory cytokines tumor necrosis factor (TNF)-α and inter- rized in five categories: (1) proliferation and cell death
leukin 1 (IL-1) – are produced by the synovium and the (apoptosis), (2) changes in synthetic activity, (3) changes
chondrocytes. In normal cartilage, there is strict regulation in degradation, (4) phenotypic modulation of the articular
of matrix turnover: a delicate balance between synthesis chondrocytes, and (5) formation of osteophyte. A repre-
and degradation. In OA, however, this balance is dis- sentation of these responses is shown in Fig. 1.
turbed, with both degradation and synthesis usually
enhanced. The inflammatory cytokines IL-1, TNF-α, IL-17, Cell proliferation and programmed cell death
and IL-18 act to increase synthesis of matrix metallopro- Many studies [13–16] have shown that there is a very low
teinases (MMPs), decrease MMP enzyme inhibitors, and proliferative activity in osteoarthritic chondrocytes, in con-
decrease extracellular matrix synthesis. The anabolic trast to normal articular chondrocytes, which have essen-
cytokines IGF-I, TGF-β1, 2, and 3, fibroblast growth tially no such activity. The activity seen in OA
factors (FGFs) 2, 4, and 8, and the BMPs act to stimulate chondrocytes might be due to better access of chondro-
extracellular matrix synthesis. It is believed that the pro- cytes to proliferative factors from the synovial fluid due to
duction of the catabolic and anabolic cytokines activates fissuring or loosening of the collagen network [13] or due
the chondrocytes; however, no single cytokine can stimu- to the damage to the collagen matrix itself [17]. In any
late all the metabolic reactions observed in OA. Recent case, proliferation of chondrocytes is most probably the
reviews explore in detail the role of cytokines and growth biological activity that causes chondrocyte clustering, a
factors in the pathogenesis of OA [5,6]. characteristic feature of OA cartilage.

Chondrocytes of articular cartilage produce and retain sig- Several authors have suggested that cell death is a central
nificant amounts of active and inactive BMPs, known to feature in osteoarthritic cartilage degeneration, as it is in
increase extracellular matrix synthesis and induce chon- the terminal hypertrophic zone of the growth plate [18–21].
drogenesis and osteogenesis. For example, both normal Recently, it was reported that apoptotic cell death is a
and OA chondrocytes synthesize and retain BMP-7 (also dominant event in the degeneration of osteoarthritic carti-
called OP-1 [osteogenic protein 1]) [7]. BMP-7 is found in lage, although the results are not in good agreement: for
two forms: an active form generated by intracellular prote- example, cell death in cartilage samples ranged from 5 to
olytic cleavage, and an inactive precursor form (pro- 11% and in patients with OA, from 22 to 51% of all cells
BMP-7) [8]. Whereas the detection of mRNA encoding [22–26]. We think it is very likely that these numbers are
BMP-7 appeared to be the same in OA and normal adult overestimates of the extent of apoptosis in cartilage,
tissues, the level of mature BMP-7 protein was downregu- because if they are correct, other biosynthetic parameters
lated in OA cartilage while the pro-BMP-7 remained high. of OA would be impossible; indeed even ‘normal’ cartilage
In OA cartilage, mature BMP-7 was detected in the super- would soon lose the capacity to undergo biosynthesis. In
ficial layer, whereas the pro form was primarily in the deep theory, a major degree of cell death would easily lead to a
layer. These results point to the possibility that one way in failure of turnover of the cartilage matrix, because chondro-
which proteinases could regulate anabolic activities is cytes are the only source of synthesis of matrix compo-
through the conversion of pro-BMPs to mature BMPs, nents in articular cartilage and there is no renewal of
converting inactive BMP to active BMP, which can then chondrocyte population. In our studies (T Aigner, unpub-
stimulate matrix synthesis. lished findings), we have confirmed that apoptosis occurs
in osteoarthritic cartilage, but at a very low rate with
Other molecular influences of cartilage degradation are approximately 0.1% of the total cell population apoptotic at
beginning to emerge that have been found to be a result a given time point, indicating that the death of chondro-
of initial molecular breakdown. It is now known that frag- cytes has only a limited impact on the pathology of
ments of fibronectin can induce expression of metallopro- osteoarthritis [13,15,27]. The only zone in which a large
teinases and matrix degradation in chondrocytes [9]. The number of empty lacunae, indicative of cell death, has been
molecular mechanism is probably the induction of found by us or others was the calcified cartilage layer
enhanced gene expression of collagenase and stromelysin [28,29]. The greatly reduced number of living chondro-
[10]. More recently, a fragment of link protein, part of the cytes in this cartilage zone does not seem to impair articu-
large proteoglycan aggregate in cartilage, was found to lar cartilage in normal conditions, but might be detrimental
stimulate proteoglycan and collagen synthesis in cartilage in more advanced stages of osteoarthritis, when this zone
explant culture [11]; consequently the fragments of is considerably enlarged and represents a higher propor-
protein degradation may stimulate the cells to attempt to tion of the residual cartilage. Because apoptotic cells are
repair the matrix, as proposed by Hering [12]. not removed effectively from cartilage, the products of cell
 Available online http://arthritis-research.com/content/3/2/107

Figure 1 osteoarthritic cartilage. The techniques used did not allow

detection of differences between cells of different carti-
lage zones. Our own analyses in situ showed that the loss
of fixed charges (due to aggrecan glycosaminoglycan side

commentary
chains) occurs in the upper zones of osteoarthritic carti-
lage, in which the cells downregulated their expression of
matrix components, in particular of aggrecan: at the same
time, the cells of the deeper zones are still activated [43].
In fact, the hyperactivity of matrix synthesis was restricted
to the chondrocytes of the middle and deeper zones of
osteoarthritic cartilage, where the extracellular matrix was
histochemically still intact and no major loss of proteogly-
can was detectable. This explains, at least in part, the loss
of proteoglycan content in the upper zone, particularly if
one assumes that the diffusion capacity of aggrecan
monomers is limited and enhanced synthesis in one zone

review
cannot compensate for the failure of synthesis in other
zones. Notably, even in specimens with a very high Mank-
in’s grade (> 8), suggesting an advanced disease state,
some chondrocytes showed strong anabolic activity and
Chondrocyte response to injury. (a) Injury and response. Mechanical thus kept their capacity to be anabolically active.
insult, joint instability and inflammatory (generally catabolic) or anabolic
cytokines can cause matrix activation, cell proliferation, apoptosis and Degradative enzymes
eventually matrix destruction. Proteoglycan fragments (PG) are lost
from the matrix. (b) Phenotypic modulation. Chondrocyte activation
Articular cartilage chondrocytes are reported to synthesize
can result in modulation of gene expression resulting in different many MMPs, namely, MMPs 1, 2, 3, 7, 8, 13, and 14
patterns of protein synthesis characteristic of chondrocyte [44–46], as well as a variety of other serine and cysteine
development, fibroblasts ‘dedifferentiation’, hypertrophy (as seen in the proteinases [47]. Most of these enzyme activities are

reports
growth plate) or regeneration of mature cartilage.
increased in OA, whether by the mechanism of increased
synthesis, increased activation of proenzymes by other
MMPs or plasmin, or decreased inhibitor activity. In nearly
death such as pyrophosphate and precipitated calcium all OA cells, MMP-3 (stromelysin), MMP-8 (collagenase-2),
may contribute to pathologic cartilage degradation. and MMP-13 (collagenase-3) were elevated. Many of these
MMPs are stimulated by exposure of the cells to inflamma-
The free radical nitric oxide (NO) has been implicated as a tory cytokines [48]. To agonize the effects of MMPs,
biological mediator in OA [30]. Articular chondrocytes expression levels of inhibitors such as tissue inhibitor of
produce the inducible enzyme nitric oxide synthase metalloproteinases (TIMP)-1 are reduced in OA and
(NOS), and both NO and NOS are synthesized in OA. The rheumatoid arthritis [49,44,50], although the ratio of total

primary research
role of NO in OA is not known, but it can inhibit proteogly- MMPs to total inhibitors is not really known. In 92% of OA
can synthesis in vitro and can inhibit chondrocytes’ cases in one study [51], MMP-7 (matrilysin), an enzyme
response to IGF-I [31]; in addition, some studies suggest with a wide range of susceptible proteins, was localized in
that it may play a role in apoptosis of chondrocytes and chondrocytes, mainly those in the superficial and transi-
synovial cells [32,33]. tional zones. Approximately 30% of the total chondrocytes
were immunostained in the positive OA cartilage samples.
Metabolic activation and hypoanabolism The results of mRNA analysis were consistent with the
In osteoarthritic cartilage, a number of biochemical studies localization of protein. The noncollagenase enzymes could
have demonstrated enhanced synthesis of extracellular act to disrupt the matrix, rendering it weaker and more sus-
matrix components [34–42]. Chondrocytes attempt to ceptible to hydration.
repair the damaged matrix by increasing their anabolic
meeting abstracts

activity. Despite this increased activity, a net loss of pro- The degradation of type II collagen has been studied
teoglycan content is one of the hallmarks of all stages of extensively by the team of Dr Robin Poole, who have
osteoarthritic cartilage degeneration [15]. This observa- shown that MMP-13 is the enzyme responsible for most of
tion has led to the assumption that overall enzymatic the collagen degradation [52]. In addition, MMP-3 can
degradation of matrix components might be the reason for cleave in the nonhelical telopeptide of type II and type IX
the metabolic imbalance. However, most previous studies collagens [53], leading to the disruption of a collagen
were based on an overall measurement of chondrocyte crosslink. This cleavage could result in a disrupted fibril
behavior or matrix composition within the whole structure and, consequently, disrupted fibril function.
Arthritis Research Vol 3 No 2 Sandell and Aigner

Indeed, Bonassar and associates have shown that treat- Classically, chondrocyte phenotypes are categorized
ment of cartilage plugs in vitro with stromelysin causes largely by subtyping of collagen gene expression
marked swelling of the tissue, whereas treatment with [64,65]. Thus, chondroprogenitor cells are character-
trypsin does not [54]. We have recently shown that the ized by the expression of the alternative splice variant of
type II collagen telopeptide can also be cleaved by MMPs type II collagen, type IIA procollagen (COL2A) [66].
7, 9, 13, and 14; this finding indicates the presence in OA Mature chondrocytes express the typical cartilage colla-
of a host of enzyme candidates capable of disrupting the gen types II (COL2B), IX, and XI as well as aggrecan
collagen network [55]. Disruption of this network will and link protein [67–69]. Hypertrophic chondrocytes
eventually lead to destabilization of the joint. Evidence for are marked by the expression of type X collagen. These
disrupted collagen structure in the pathophysiology of OA cells are found in the lowest zone of the cartilage of the
also comes from genetic studies showing that mutations fetal growth plate [70,71] and in the calcified zone of
in type II collagen lead to an unstable collagen network adult cartilage thought to be a remnant of the lower
and eventually to premature OA [56,57]. hypertrophic zone of the fetal growth-plate cartilage
[72]. Chick chondrocytes can undergo post-hyper-
Two new families of degradative enzymes have been trophic differentiation to osteoblast-like cells, expressing
detected in articular cartilage. Protein and mRNA for type I collagen [73–75].
ADAM-10 (A Disintegrin-like And Metalloproteinase-like
domain) was found in the most fibrillated areas of OA carti- In our laboratories, we performed in situ expression analy-
lage, especially in the cell clusters. Probably more impor- ses in normal and osteoarthritic cartilage specimens,
tantly, two new enzymes, called aggrecanase 1 and 2, have using the markers for chondrocyte differentiation, colla-
been isolated that are ADAMs enzymes with an additional gen type II and aggrecan (activated functional chondro-
thrombospondin domain (ADAM-TS) capable of binding to cytes), collagen types I and III (dedifferentiated
chondroitin sulfate. The MMPs and aggrecanases cleave chondrocytes), collagen type IIA (chondroprogenitor
aggrecan at distinct sites in the core protein [58]. cells), and collagen type X (hypertrophic chondrocytes).
Activated chondrocytes were found mostly in the middle
Cysteine peptidases, primarily cathepsins, have recently zones of osteoarthritic cartilage. These cells also
been found in OA cartilage and subchondral bone. expressed type IIA procollagen and deposited it primarily
Cathepsins L and K were localized subchondrally in asso- in the cell-associated cartilage. This indicates that on the
ciation with cathepsin B, in osteophytes, in zones under- molecular level, a significant proportion of adult articular
going bone remodeling and at sites of inflammation, chondrocytes starts to re-express a chondroprogenitor
whereas cathepsin B was present and active in cartilage, phenotype in osteoarthritic cartilage degeneration, which
particularly at sites where matrix neosynthesis takes place is comparable to the chondroprogenitor phenotype
[59]. Inhibition of these cysteine enzymes had an effect on observed in fetal skeletal development [66,76]. Cells
cartilage breakdown, indicating that they may play a role in expressing type III collagen were mainly found in the
the cascade of events leading to matrix degradation. upper middle zone. Interestingly, a reversion to a fetal
phenotype and the reinitiation of fetal skeletal develop-
Phenotypic alterations of the chondrocytic mental processes also occurs in the deepest zones of
phenotype osteoarthritic cartilage: here, the cells start to express
Potential phenotypic changes are characteristic of chon- type X collagen [77], which is a specific marker for hyper-
drocytes. Many studies have shown changes in phenotype trophy of growth-plate chondrocytes [78,70]; apoptosis
during chondrocyte differentiation in vivo in the fetal occurs; and the cartilage matrix calcifies: all these events
growth-plate cartilage and of chondrocyte behavior in are processes taking place in the lowest zone of fetal
vitro. Several factors, such as retinoic acid, bromo- growth-plate cartilage.
deoxyuridine, and IL-1, induce so-called ‘dedifferentiation’,
or modulation of the chondrocyte phenotype to a fibrob- The uppermost chondrocytes of OA cartilage often do not
last-like phenotype. The chondrocytes stop expressing demonstrate expression of any of the collagen types inves-
aggrecan and collagen type II, though they are still very tigated. This pattern is not replicated by the established
active cells and express collagen types I, III, and V modulations of the chondrocyte phenotype known in vivo
[60–63]. This example clearly demonstrates the implica- and in vitro. None of the discussed marker genes were
tions of phenotypic alterations of chondrocytes: despite expressed by the chondrocytes in the upper zone of
potentially high synthetic activity, dedifferentiated chon- osteoarthritic cartilage [77,79] and no really specific
drocytes do not express cartilage-specific anabolic genes markers have been established yet for these cells,
such as aggrecan or type II collagen. Therefore, in addition although one good candidate could be the cartilage
to deactivation, phenotypic alteration represents another surface protein gp-30 [80]. This stresses the need to
potential reason for anabolic failure of chondrocytes in establish a broader gene expression profile by modern
osteoarthritic cartilage. screening technologies.
 Available online http://arthritis-research.com/content/3/2/107

Secondary cartilage formation (osteophytes) Conclusions

One of the most remarkable and consistent features of The cellular response in OA is complex, and the more
joints affected by OA, whether naturally occurring or information becomes available, the more complex it
experimentally induced, is the development of prominent seems. Of integral importance is the question of why the

commentary
osteochondral nodules known as osteophytes (also called cartilage retains function for many years, and then begins
osteochondrophytes or chondro-osteophytes). Indeed, the to erode rapidly. A great deal of information in OA has
presence of osteophytes in a joint, more than any other come from studies at joint replacement and in animal
pathological feature, distinguishes OA from other arthri- models; however, such studies focus on the beginning
tides [81]. It seems likely that both mechanical and and end of the process. More studies are needed that fill
humoral factors are involved in stimulating the formation of the gaps in between by studying high-risk populations,
osteophytes. Osteophytes are an example of new carti- mild ongoing OA in humans, and following animal models
lage and bone development in OA joints and arise from to end-stage OA. Preliminary studies in this area are
tissue associated with the chondro-synovial junction or encouraging, showing that the information obtained from
from progenitor cells residing in the perichondrium both animal models and end-stage human OA is valid. Our
[82–84] – indicating that there is a population of pluri- challenge in the future will be to sort out the primary and
potential cells that is responsive to the mechanical and secondary stimuli and cellular responses and determine at

review
humoral sequelae of joint injury [84]. Though the exact what level the disease process can be attenuated.
functional significance of osteophyte growth remains
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