Cartilage Disorders Research Articles

Adenoviral transduction is more efficient in alginate-derived chondrocytes than in monolayer chondrocytes

Gene transfer into cultured chondrocytes by using adenoviral vectors has potential applications in treating cartilage disorders. The present study was undertaken to compare and optimize two chondrocyte culture conditions for adenoviral transduction efficacy by using primary human articular chondrocytes cultivated either directly in a monolayer condition or as outgrowths from alginate-stored chondrocyte cultures. Isolated primary chondrocytes from human articular cartilage were either immediately transduced with an EGFP (enhanced green fluorescent protein)-gene-bearing adenoviral vector (1,000 and 3,000 virus particles/cell) or cultured in alginate before transduction. Immunohistochemistry and flow cytometric analysis were employed to determine the expression of extracellular matrix proteins and of the alphavbeta5 integrin receptor involved in adenoviral cell entry. Monolayer chondrocytes exhibited moderate transduction rates (mean 22.2% and 46.9% EGFP-positive cells at 1,000 and 3,000 virus particles/cell by 72 h post-transduction), whereas alginate-derived chondrocytes revealed significantly higher transduction efficacies (95.7% and 99%). Both monolayer and alginate-derived chondrocytes expressed alphavbeta5 integrin, type II collagen and cartilage proteoglycans. The mean fluorescence intensity of type II collagen was significantly higher in the alginate-derived chondrocytes, whereas that of alphavbeta5 integrin was higher in the monolayer chondrocytes. Our results indicate that transduction efficacy is independent of alphavbeta5 integrin expression levels in chondrocytes. Moreover, adenoviral transduction of alginate-derived chondrocytes is more efficient than that for monolayer chondrocytes and may be a suitable tool to achieve sufficient numbers of transduced and differentiated chondrocytes for experimental applications and cartilage repair.

Large-scale gene expression profiles, differentially represented in osteoarthritic synovium of the knee joint using cDNA microarray technology

Osteoarthritis (OA) is one of the most common age-related chronic disorders of articular cartilage, joints and bone tissue. Diagnosis of OA commonly depends on clinical and radiographic findings. However, changes in cartilage associated with the early stage of OA cannot be detected using radiographs, because significant cartilage degeneration must occur before radiographic findings show alterations of the appearance of cartilage. To identify new biomarkers of OA, we analysed gene expression profiles of synovium from 43 patients with OA, ten patients with rheumatoid arthritis (RA), and eight non-OA/non-RA patients using a novel cDNA microarray chip. We identified 21 genes with simultaneous significant differences in expression between OA and non-OA/non-RA groups and between OA and RA groups. Linear discriminant analysis showed that the three groups could be well separated using those 21 genes. Statistical analysis also revealed that several of the 21 genes were associated with disease progression and clinical presentation. The graphical modelling method indicated that some of the 21 genes are significantly associated with a particular clinical presentation, suggesting biological relationships among those genes. This is the first report of the use of cDNA microarray technology to create large-scale gene expression profiles differentially expressed in situ in OA synovium of the knee joint.

Influence of cellular microenvironment and paracrine signals on chondrogenic differentiation

Articular cartilage disorders and injuries often result in life long chronic pain and compromised quality of life, thus regeneration of articular cartilage is a persistent challenge to medical science. One of the most promising therapeutic approaches is cell based tissue engineering which provides a healthy population of cells to the injured site and requires differentiated chondrocytes from the uninjured site as base material. Use of healthy chondrocytes has several limitations and an excellent alternative cell population could be adult marrow stromal cells/mesenchymal stem cells (MSCs) which are known to possess extensive proliferation potential and proven capability to differentiate into chondrocytes. Both, in vivo and in vitro pliability of MSCs and chondrocytes greatly depends on their microenvironment. Gene and protein expression profiles of both the cell types can be altered by soluble factors from surrounding tissue/ cells or by direct cellular contact. For MSC or chondrocyte-based cartilage repair, inhibition of hypertrophy and stabilization of the cartilaginous phenotype in the implant is a prerequisite for success and long lasting vitality of the repaired tissue.

Disorders of acetabular labrum and articular cartilage in hip dysplasia: evaluation using isotropic high-resolutional CT arthrography with sequential radial reformation

Acetabular labral tear may predispose to adjacent articular cartilage disorder and hip osteoarthritis in patients with hip dysplasia. We evaluated the diagnostic ability of isotropic computed tomography (CT) arthrography with radial reformation technique for detection of acetabular labral and articular cartilage disorders, and evaluate those interactions in hip dysplasia. Forty-one hips in 29 patients with hip dysplasia received CT arthrography with isotropic spatial resolution of 0.5mm. After processing of multiplanar radial reformation over the whole acetabular circumference, frequencies of labral tear and acetabular cartilage disorder were evaluated at six divided zones of the weight-bearing areas. Of the 41 hips, 20 hips underwent arthroscopic examinations, and sensitivity, specificity and accuracy for detecting labral tear and acetabular cartilage disorder by CT arthrography were calculated using the arthroscopic findings as the standard of reference. The sensitivity, specificity and accuracy of CT arthrography were 97%/87%/92% for labral tear and 88%/82%/85% for acetabular cartilage disorder, respectively, using arthroscopic findings as the reference. The CT arthrography showed significantly higher frequency of labral and acetabular cartilage disorders at the anterior zones. Those zones with labral tear had significantly higher frequency of adjacent cartilage disorder than zones without labral tear. Isotropic CT arthrography with radial reformation technique allowed simultaneous, accurate assessment of labral and cartilage disorders in the whole acetabular circumference. Our findings indicated that labral tear is closely associated with adjacent cartilage disorder in hip dysplasia.

Axis Correction in Cartilage Repair

Angular deformity of the lower limb, either physiological or after incorrect healing of lower limb fractures may cause severe degenerative changes and thus functional impairment of both hip, knee and ankle joints. Therefore, early correction of the axis is strictly indicated. This article focuses on the correction of axial deformities especially when using “bioresurfacing techniques” in cartilage disorders like microfracturing, autologous osteochondral transplantation and autologous chondrocyte transplantation which is reported to bring about marked advantages for the regeneration of the articular surface. Anatomic considerations and principles of correction osteotomy are discussed, three rules of osteotomy in general and in osteotomies around the knee are postulated.

Deletions in the COL10A1 gene are not associated with skeletal changes in dogs

Type 10 collagen alpha 1 (COL10A1) is a short-chain collagen of cartilage synthesized by chondrocytes during the growth of long bones. COL10A1 mutations, which frequently result in COL10A1 haploinsufficiency, have been identified in patients with Schmid metaphyseal chondrodysplasia (SMCD), a cartilage disorder characterized by short-limbed short stature and bowed legs. Similarities between SMCD and short stature in various dog breeds suggested COL10A1 as a candidate for canine skeletal dysplasia. We report the sequencing of the exons and promoter region of the COL10A1 gene in dog breeds fixed for a specific type of skeletal dysplasia known as chondrodysplasia, breeds that segregate the skeletal dysplasia phenotype, and control dogs of normal stature. Thirteen single nucleotide polymorphisms (SNPs), one insertion, and two deletions, one of which introduces a premature stop codon and likely results in nonsense-mediated decay and the degradation of the mutant allele product, were identified in the coding region. There appear to be no causal relationships between the polymorphisms identified in this study and short stature in dogs. Although COL10A1 haploinsufficiency is an important cause of SMCD in humans, it does not seem to be responsible for the skeletal dysplasia phenotype in these dog breeds. In addition, homozygosity for the nonsense allele does not result in the observed canine skeletal dysplasia phenotype.

Effect of IGF-I in the Chondrogenesis of Bone Marrow Mesenchymal Stem Cells in the Presence or Absence of TGF-β Signaling

A novel role for IGF-I in MSC chondrogenesis was determined. IGF-I effects were evaluated in the presence or absence of TGF-beta signaling by conditionally inactivating the TGF-beta type II receptor. We found that IGF-I had potent chondroinductive actions on MSCs. IGF-I effects were independent from and additive to TGF-beta. Mesenchymal stem cells (MSCs) can be isolated from adult bone marrow (BM), expanded, and differentiated into several cell types, including chondrocytes. The role of IGF-I in the chondrogenic potential of MSCs is poorly understood. TGF-beta induces MSC chondrogenic differentiation, although its actions are not well defined. The aim of our study was to define the biological role of IGF-I on proliferation, chondrogenic condensation, apoptosis, and differentiation of MSCs into chondrocytes, alone or in combination with TGF-beta and in the presence or absence of TGF-beta signaling. Mononuclear adherent stem cells were isolated from mouse BM. Chondrogenic differentiation was induced by culturing high-density MSC pellets in serum- and insulin-free defined medium up to 7 days, with or without IGF-I and/or TGF-beta. We measured thymidine incorporation and stained 2-day-old pellets with TUNEL, cleaved caspase-3, peanut-agglutinin, and N-cadherin. Seven-day-old pellets were measured in size, stained for proteoglycan synthesis, and analyzed for the expression of collagen II and Sox-9 by quantitative real time PCR. We obtained MSCs from mice in which green fluorescent protein (GFP) was under the Collagen2 promoter and determined GFP expression by confocal microscopy. We conditionally inactivated the TGF-beta type II receptor (TbetaRII) in MSCs using a cre-lox system, generating TbetaRII knockout MSCs (RIIKO-MSCs). IGF-I modulated MSC chondrogenesis by stimulating proliferation, regulating cell apoptosis, and inducing expression of chondrocyte markers. IGF-I chondroinductive actions were equally potent to TGF-beta1, and the two growth factors had additive effects. Using RIIKO-MSCs, we showed that IGF-I chondrogenic actions are independent from the TGF-beta signaling. We found that the extracellular signal-related kinase 1/2 mitogen-activated protein kinase (Erk1/2 MAPK) pathway mediated the TGF-beta1 mitogenic response and in part the IGF-I proliferative action. Our data, by showing the role of IGF-I and TGF-beta1 in the critical steps of MSC chondrogenesis, provide critical information to optimize the therapeutic use of MSCs in cartilage disorders.

Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects

The mammalian Nell1 gene encodes a protein kinase C-beta1 (PKC-beta1) binding protein that belongs to a new class of cell-signaling molecules controlling cell growth and differentiation. Over-expression of Nell1 in the developing cranial sutures in both human and mouse induces craniosynostosis, the premature fusion of the growing cranial bone fronts. Here, we report the generation, positional cloning and characterization of Nell1(6R), a recessive, neonatal-lethal point mutation in the mouse Nell1 gene, induced by N-ethyl-N-nitrosourea. Nell1(6R) has a T-->A base change that converts a codon for cysteine into a premature stop codon [Cys(502)Ter], resulting in severe truncation of the predicted protein product and marked reduction in steady-state levels of the transcript. In addition to the expected alteration of cranial morphology, Nell1(6R) mutants manifest skeletal defects in the vertebral column and ribcage, revealing a hitherto undefined role for Nell1 in signal transduction in endochondral ossification. Real-time quantitative reverse transcription-PCR assays of 219 genes showed an association between the loss of Nell1 function and reduced expression of genes for extracellular matrix (ECM) proteins critical for chondrogenesis and osteogenesis. Several affected genes are involved in the human cartilage disorder Ehlers-Danlos Syndrome and other disorders associated with spinal curvature anomalies. Nell1(6R) mutant mice are a new tool for elucidating basic mechanisms in osteoblast and chrondrocyte differentiation in the developing skull and vertebral column and understanding how perturbations in the production of ECM proteins can lead to anomalies in these structures.

P168 INCREASED AGGREGATION OF PROTEOGLYCAN COMPLEXES BY CHONDROITIN SULFATES ADDED TO IL-1 TREATED CHONDROCYTES IS ASSOCIATED WITH DECREASED ADAMTS-5 EXPRESSION

with post hoc Bonferroni corrected t-tests were used to examine differences between unstrained and strained constructs, as indicated by an asterix in figure 1. In all cases, a level of 5% was considered statistically significant. Results: Figure 1 presents the magnitude of stimulation or inhibition of •NO release, cell proliferation and proteoglycan synthesis by dynamic compression under the different treatment conditions. The data presented demonstrate that in the absence of the inhibitor, dynamic compression suppressed •NO release. Treatment with gadolinium and suramin caused a compressioninduced upregulation of •NO release, a response abolished with apyrase. Compression-induced stimulation of cell proliferation was reversed with gadolinium, suramin or apyrase. By contrast, compression-induced stimulation of proteoglycan synthesis was abolished under all treatment conditions. Conclusions: The activation of a purinergic pathway is important in suppressing the release of •NO and stimulation of proteoglycan synthesis. Indeed, high levels of •NO could trigger a downstream catabolic response and inhibit cell proliferation in mechanically stimulated cells. The current study demonstrates for the first time the importance of a purinergic signalling pathway in mediating the metabolic response to dynamic compression and suppressing an inflammatory effect. Further characterisation of this important pathway may identify potential pharmacological targets for the treatment of cartilage disorders like osteoarthritis.

Mutations ofCOL10A1 in Schmid metaphyseal chondrodysplasia

Schmid metaphyseal chondrodysplasia (SMCD) is a dominantly inherited cartilage disorder caused by mutations in the gene for the hypertrophic cartilage extracellular matrix structural protein, collagen X (COL10A1). Thirty heterozygous mutations have been described, about equally divided into two mutation types, missense mutations, and mutations that introduce premature termination signals. The COL10A1 mutations are clustered (33/36) in the 3' region of exon 3, which codes for the C-terminal NC1 trimerization domain. The effect of COL10A1 missense mutations have been examined by in vitro expression and assembly assays and cell transfection studies, which suggest that a common consequence is the disruption of collagen X trimerization and secretion, with consequent intracellular degradation. The effect of COL10A1 nonsense mutations in cartilage tissue has been examined in two patients, demonstrating that the mutant mRNA is completely removed by nonsense mediated mRNA decay. Thus for both classes of mutations, functional haploinsufficiency is the most probable cause of the clinical phenotype in SMCD.

Tumor necrosis factor alpha and epidermal growth factor act additively to inhibit matrix gene expression by chondrocyte

The failure of chondrocytes to replace the lost extracellular matrix contributes to the progression of degenerative disorders of cartilage. Inflammatory mediators present in the joint regulate the breakdown of the established matrix and the synthesis of new extracellular matrix molecules. In the present study, we investigated the effects of tumor necrosis factor alpha (TNF-α) and epidermal growth factor (EGF) on chondrocyte morphology and matrix gene expression. Chondrocytes were isolated from distal femoral condyles of neonatal rats. Cells in primary culture displayed a cobblestone appearance. EGF, but not TNF-α, increased the number of cells exhibiting an elongated morphology. TNF-α potentiated the effect of EGF on chondrocyte morphology. Individually, TNF-α and EGF diminished levels of aggrecan and type II collagen mRNA. In combination, the effects of TNF-α and EGF were additive, indicating the involvement of discrete signaling pathways. Cell viability was not compromised by TNF-α or by EGF, alone or in combination. EGF alone did not activate NF-κB or alter NF-κB activation by TNF-α. Pharmacologic studies indicated that the effects of TNF-α and EGF alone or in combination were independent of protein kinase C signaling, but were dependent on MEK1/2 activity. Finally, we analyzed the involvement of Sox-9 using a reporter construct of the 48 base pair minimal enhancer of type II collagen. TNF-α attenuated enhancer activity as expected; in contrast, EGF did not alter either the effect of TNF-α or basal activity. TNF-α and EGF, acting through distinct signaling pathways, thus have additive adverse effects on chondrocyte function. These findings provide critical insights into the control of chondrocytes through the integration of multiple extracellular signals.

Position of single amino acid substitutions in the collagen triple helix determines their effect on structure of collagen fibrils

Collagen II fibrils are a critical structural component of the extracellular matrix of cartilage providing the tissue with its unique biomechanical properties. The self-assembly of collagen molecules into fibrils is a spontaneous process that depends on site-specific binding between specific domains belonging to interacting molecules. These interactions can be altered by mutations in the COL2A1 gene found in patients with a variety of heritable cartilage disorders known as chondrodysplasias. Employing recombinant procollagen II, we studied the effects of R75C or R789C mutations on fibril formation. We determined that both R75C and R789C mutants were incorporated into collagen assemblies. The effects of the R75C and R789C substitutions on fibril formation differed significantly. The R75C substitution located in the thermolabile region of collagen II had no major effect on the fibril formation process or the morphology of fibrils. In contrast, the R789C substitution located in the thermostable region of collagen II caused profound changes in the morphology of collagen assemblies. These results provide a basis for identifying pathways leading from single amino acid substitutions in collagen II to changes in the structure of individual fibrils and in the organization of collagenous matrices.

An articular cartilage contact model based on real surface geometry

Abnormal, excessive stresses acting on articular joint surfaces are speculated to be one of the causes for joint degeneration. However, articular surface stresses have not been studied systematically, since it is technically difficult to measure in vivo contact areas and pressures in dynamic situations. Therefore, we implemented a numerical model of articular surface contact using accurate surface geometries. The model was developed for the cat patellofemoral joint. We demonstrated that small misalignments of the patella relative to the femur change the joint contact mechanics substantially for a given external load. These results suggest that misalignment might be studied as one of the factors causing articular cartilage disorder and joint degeneration.

Experimental ischemia of porcine growth cartilage produces lesions of osteochondrosis

Osteochondrosis is a disorder of growth cartilage in which a focal failure of blood supply has been proposed as an important initiating factor. In the present study we investigated the effect on epiphyseal growth cartilage of experimentally interrupting the blood supply to a limited area of the distal femur of growing pigs. In 12 pigs, a thin full-thickness cartilage slab was removed from the abaxial margin of the medial condyle, thereby transecting a limited number of cartilage canals. The pigs were culled 1, 2, 3, 7, 14, 21 and 29 days post-surgery. The condylar cartilage was studied histologically, immunohistologically and by use of the TUNEL method. The transection induced cellular death of cartilage canal elements followed by cellular death of chondrocytes within the deep layers of the resting zone of the epiphyseal growth cartilage. However, in the superficial layers of the resting zone, chondrocytes appeared to proliferate into and subsequently chondrify some of the necrotic cartilage canals. The dying and dead cells were TUNEL-positive, but active caspase 3-negative. The loss of vascular supply induced increased VEGF-immunostaining in chondrocytes surrounding the affected area. We conclude that transection of cartilage canals produces chondronecrosis in the deep resting zone of the epiphyseal growth cartilage similar to that observed in spontaneously occurring osteochondrosis.

Overexpression of human fibroblast growth factor 2 stimulates cell proliferation in an ex vivo model of articular chondrocyte transplantation.

Genetically engineered chondrocytes could be used to enhance cartilage repair. Fibroblast growth factor 2 (FGF-2) is a mitogen for chondrocytes and may be a candidate for gene transfer approaches to stimulate chondrocyte proliferation. In the present study, we tested the hypothesis that human FGF-2 (hFGF-2) gene transfer into articular chondrocytes modulates cell proliferation in an ex vivo model of chondrocyte transplantation. Transfection of articular chondrocytes with an expression plasmid vector carrying the cDNA for hFGF-2 under the control of the cytomegalovirus promoter/enhancer mediated transgene expression and synthesis of biologically relevant amounts of the recombinant hFGF-2 protein. Articular chondrocytes transfected with the Escherichia coli beta-galactosidase (lacZ) gene or a hFGF-2 cDNA were transplanted onto the surface of articular cartilage explants. The tissue formed by the chondrocytes expressing hFGF-2 was thicker and contained more cells than control cultures. Quantitative analysis of [(3)H]thymidine and [(35)S]sulfate incorporation in composite cultures revealed that hFGF-2 transfection stimulated mitogenic activity in the new tissue but did not augment matrix glycosaminoglycan synthesis. These data support the concept that chondrocytes overexpressing a hFGF-2 cDNA selectively modulate cell proliferation in an ex vivo model of chondrocyte transplantation. These results suggest that therapeutic hFGF-2 gene transfer may be applicable for the treatment of articular cartilage disorders, such as traumatic defects in which cellular repopulation is a therapeutic goal.

Influence of floor type and stocking density on leg weakness, osteochondrosis and claw disorders in slaughter pigs

AbstractThe effects of floor type and stocking density on leg weakness, osteochondrosis and claw disorders in slaughter pigs were studied. Three hundred pigs were housed in pens with either solid floors with plenty of straw, solid floors without straw or fully slatted floors at either high (0·65 m2per pig) or low (1·2 m2per pig) stocking density from 25 to 105 kg. In each pen half of the pigs were boars and half gilts of the breeds Landrace and Yorkshire ✕ Landrace crossbred. There was no difference in growth rate between the three floor types. The growth rate of the boars was higher at low compared with high stocking density, while no effect of stocking density was seen in the gilts. The prevalence of leg weakness and claw disorders was different for the various floor types, while no effect of floor type could be found on joint changes. With regard to leg weakness, slatted flooring was significantly worse than solid floors with or without straw for standing under position on hind legs, while pens with plenty of straw were significantly better than the other floor types with regard to stiff movement and forelegs turned out. A calculated sum of the nine leg weakness symptoms showed that pens with straw were the best followed by solid floor without straw, while slatted floors were the worst. Regarding claw disorders, solid floors without straw were the worst. High stocking density affected four leg weakness variables (buck-kneed forelegs, turned-out fore- and hind legs, standing under position on hind legs), one joint change and three claw disorders negatively. Boars scored worse than gilts with regard to one leg weakness trait and one claw disorder and thickening of cartilage in two joints. Differences between breeds differed for the examined variables. Claw hardness was affected by floor type with regard to medial claws, which were softer on slatted floors. The hind claws were softer than the foreclaws on the volar surface, while there was no difference between the hardness of the topside of the fore- and hind claws. Claw hardness was not affected by sex. In conclusion, it can be said that the examined floor types do not have the same effect on the different aspects of leg weaknesses and claw disorders. Thus, clinical leg problems are worst on slatted floors and best in pens with straw, but claw disorders are worst on solid floors without straw. Further, high stocking density specifically affects the clinical leg weaknesses and claw disorders. Joint changes were not affected by floor type or stocking density.

Genetic contribution to cartilage volume in women: a classical twin study.

A classical twin study was performed to assess the relative contribution of genetic and environmental factors to cartilage volume. The subjects were 136 adult female twins: 31 monozygotic and 37 dizygotic twin pairs. The subjects had a T2-weighted fat-saturated sagittal gradient echo MRI performed of their right knee. Femoral, tibial and patella cartilage volumes were measured using 3D Slicer, a piece of software that facilitates semi-automatic segmentation, generation of three-dimensional surface models and quantitative analysis. The intraclass correlations were calculated, and maximum-likelihood model fitting was used to estimate genetic and environmental variance components. All variables were adjusted for age, BMI and femoral condyle size. The intraclass correlations for all of the cartilage volumes assessed were higher in monozygotic than dizygotic twin pairs. The heritabilities (95% confidence intervals) obtained from model fitting were: femoral, 61% (36-77%); tibial, 76% (56-87%); patella, 66% (47-79%); and total cartilage volume, 73% (51-85%). This study provides evidence for the importance of genetic factors in determining cartilage volume. Identifying heritability is the first step on the way to finding specific genes, which may improve our insight in the pathophysiology of cartilage disorders including the etiology of complex diseases such as osteoarthritis.

Role of apoptosis inhibition in various chondrocyte culture systems

Apoptosis may limit the utility of cell-based therapies for articular cartilage disorders. We tested the hypothesis that chondrocyte apoptosis can be reduced by optimizing the conditions employed to expand chondrocyte numbers in culture. Chondrocyte apoptosis was examined in monolayer and suspension culture, in the presence of fetal bovine serum (FBS) or autologous serum, and for culture periods of 2 or 4 days. The effect of these variables was assessed by measuring cell viability, Annexin V labeling and mitochondrial membrane potential. After 2 days of culture, the greatest increase in viable cell number (3.7-fold) occurred in monolayer cultures with autologous serum. After 4 days of culture, the greatest increase in cell number (9.0-fold) occurred in monolayer cultures supplemented with FBS. By Annexin V staining, the proportion of cells undergoing apoptosis after 2 days was not affected by the type of serum used or by culture in monolayer versus suspension. After 4 days of culture, the proportion of apoptotic cells was significantly reduced (35% to 13%, p<0.02) in suspension cultures with autologous serum. Apoptosis assessed by loss of mitochondrial membrane potential was decreased in the presence of autologous serum. These data suggest that suspension culture with autologous serum is useful in simultaneously maintaining cell proliferation and minimizing apoptosis in cultured human articular chondrocytes.

Review: Clinical Variability and Genetic Heterogeneity in Multiple Epiphyseal Dysplasia

This review reports on multiple epiphyseal dysplasia (MED), first described clinically in the early part of the 20th century. Over 50 years later, we are now beginning to unravel the mystery behind the genetic mutations involved in triggering the changes in cartilage observed in this condition. In the past decade considerable progress has been made in identifying the underlying genetic defect in some forms of MED. Understanding the precise effect that these molecular changes have on the integrity of the cartilage extracellular matrix will lead the way in identifying the complex disease pathophysiology that defines MED. In addition, a greater understanding of the role and interactions of specific cartilage molecules may reveal the basis of more widespread cartilage disorders such as osteoarthritis.

Review: clinical variability and genetic heterogeneity in multiple epiphyseal dysplasia.

This review reports on multiple epiphyseal dysplasia (MED), first described clinically in the early part of the 20th century. Over 50 years later, we are now beginning to unravel the mystery behind the genetic mutations involved in triggering the changes in cartilage observed in this condition. In the past decade considerable progress has been made in identifying the underlying genetic defect in some forms of MED. Understanding the precise effect that these molecular changes have on the integrity of the cartilage extracellular matrix will lead the way in identifying the complex disease pathophysiology that defines MED. In addition, a greater understanding of the role and interactions of specific cartilage molecules may reveal the basis of more widespread cartilage disorders such as osteoarthritis.