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PubMed2004

The use of debrided human articular cartilage for autologous chondrocyte implantation: maintenance of chondrocyte differentiation and proliferation in type I collagen gels.

UNLABELLED: Autologous chondrocyte implantation (ACI) is the most promising surgical treatment for large full thickness knee joint articular cartilage (AC) defects where cells from healthy non-weight bearing area AC are multiplied in vitro and implanted into such defects. In the routine surgical procedure for symptomatic knee full thickness AC defects, damaged AC surrounding the edge and the base of such defects is usually debrided and discarded. The purpose of this study was to examine if chondrocytes from this 'debrided' AC can proliferate, synthesize a cartilage specific matrix and thus can be used for ACI. METHODS: Biopsies were retrieved from 12 patients (debrided articular cartilage: DAC, aged 35-61) and from two autopsies (normal articular cartilage: NAC, aged 21 and 25). Chondrocytes were isolated, seeded at low density in type I collagen gels and as monolayer cultures for 4 weeks without passage. RESULTS: After 4 weeks cultures in type I collagen gels, cell proliferation from DAC (18.34 +/- 1.95 fold) was similar to cells from NAC (11.24 +/- 1.02 fold). Syntheses of proteoglycan and collagen in DAC were also similar to NAC. Newly synthesized matrices in gel cultures consisted predominantly of type II collagen as shown by immuno-labelling and SDS-PAGE followed by fluorography. Chondrocytes from 'debrided human AC' cultured at low density in type I collagen gels may be used for the ACI procedure as they provide sufficient viable cell numbers for ACI and maintain their chondrocyte phenotype as they synthesize a cartilage-like matrix.

Adult↗
PubMed1982

A functional-morphological study of the tidemark region of articular cartilage maintained in a non-viable physiological condition.

Composite samples consisting of articular and calcified cartilage maintained in a non-viable physiological condition have been subjected to static compression using a system of simultaneous micromechanical testing and interference light microscopy. This, combined with transmission electron microscopy following glutaraldehyde fixation of the tissue under sustained load, has provided a unique observation of the response of the collagen framework in the tidemark region of articular cartilage to sustained compression loading. The tidemark in mature articular cartilage is seen to be highly variable in its morphological features, when viewed ultrastructurally. It incorporates variable amounts of internal stress which are relieved when the articular cartilage is separated from the calcified cartilage. Deformation of the articular cartilage can terminate abruptly at the tidemark. There is no evidence that the tidemark or calcified cartilage provided an intermediate layer between the complaint articular cartilage and the rigid subchondral bone. However, morphological evidence presented suggests that a smooth transfer of stress from the complaint to the rigid tissues could be achieved through changes in orientation and packing density of the collagen fibres in the articular cartilage adjacent to the tidemark. A variety of morphological responses of the collagen framework was observed in the tidemark region of articular cartilage following static compressive loading. In any given region, these responses were determined by (a) the local form and orientation of the tidemark; (b) the organisation of the collagen fibres; (c) the position of this region with respect to the compressive anvil. No evidence was obtained which suggested that the collagen fibres near the tidemark had a predominantly tensile role during direct compression. The observed process of compaction and collapse via a 'crimp' formation is clearly non-tensile. However, deformation involving lateral shear in regions nearer the extremities of joint contact would require that the collagen fibres provide an anchoring role and thus be subjected to tensile loading.

Animals↗
PubMed1998

Effects of methotrexate on normal articular cartilage in vitro and in vivo.

OBJECTIVE: Methotrexate (MTX) has become the disease modifying drug of choice for the treatment of rheumatoid arthritis (RA). Direct effects of MTX on articular cartilage in vivo and in vitro were studied to determine possible adverse effects of the drug. METHODS: For in vitro experiments, adult bovine articular cartilage explants were cultured in the presence of MTX (0 to 100 microM), and effects on DNA and matrix metabolism were studied. For in vivo studies, 48 adult female rabbits were treated with MTX (30 mg/kg/week intramuscularly) or placebo, respectively, for up to 12 weeks, and effects on the cartilage of the femoral condyles were assessed. RESULTS: In vitro, MTX dose dependently increased the uptake of [3H]-thymidine, and decreased incorporation of [3H]-d-uridine into chondrocytes with a half maximal effect at 0.03 microM, suggesting inhibition of thymidylate-synthetase activity by the drug. MTX also dose dependently reduced the proportion of chondrocytes in S-phase, as determined by flow cytometry. MTX did not affect LDH release from chondrocytes or the proportion of viable cells, nor did it change the rate of protein synthesis, proteoglycan synthesis, proteoglycan breakdown, or the hydrodynamic size of newly synthesised proteoglycans. In vivo, MTX did not appreciably affect proteoglycan synthesis of the chondrocytes, proteoglycan content of the cartilage matrix, density of the chondrocyte population, or histological integrity of the cartilage. CONCLUSIONS: The data suggest the absence of major adverse effects by MTX on articular cartilage proteoglycan metabolism. Chondrocyte DNA metabolism seems to be changed by MTX only in concentrations and exposition periods clearly exceeding those found in synovial fluid of RA patients receiving the commonly prescribed doses of the drug.

Animals↗
PubMed1995

Effect of exogenous hyaluronan and hyaluronan oligosaccharides on hyaluronan and aggrecan synthesis and catabolism in adult articular cartilage explants.

The addition of hyaluronan to the culture medium of explant cultures of articular cartilage was shown to suppress the synthesis of hyaluronan and aggrecan, the major proteoglycan present in cartilage, and resulted in a greater proportion of the newly synthesized aggrecan and hyaluronan appearing in the culture medium. This effect of exogenous hyaluronan on aggrecan and hyaluronan synthesis was concentration-dependent and reversible on removal of the glycosaminoglycan from the culture medium. The addition of tetra- and hexasaccharides derived from Streptomyces sp. hyaluronidase digestion of hyaluronan to explant cultures of articular cartilage did not change the rate of synthesis of aggrecan or hyaluronan or their ultimate distribution between tissue and medium. However, the addition of tetra- and hexasaccharides of hyaluronan resulted in a decrease in the rate of loss of hyaluronan from the tissue but not that of aggrecan, which remained the same as in control cultures. This suppression of the rate of loss of hyaluronan was eliminated on removal of the hyaluronan oligosaccharides from the culture medium. Analysis of the hydrodynamic size of the newly synthesized hyaluronan indicated that the presence of hyaluronan tetra- and hexasaccharides brought about an accumulation of hyaluronan of intermediate molecular mass. Since no radiolabeled hyaluronan was detected in the culture medium, it was concluded that the tetra- and hexasaccharides inhibited the internalization and intracellular catabolism of hyaluronan by the cartilage explant cultures. Regardless of whether hyaluronan or tetra- and hexasaccharides of hyaluronan were added to the culture medium, newly synthesized hyaluronan underwent depolymerization at a rate consistent with a mechanism involving oxygen-derived radicals.

Adult↗
PubMed2003

Effects of long-term exposure to glucosamine and mannosamine on aggrecan degradation in articular cartilage.

OBJECTIVE: To investigate the effect of long-term exposure to glucosamine or mannosamine on the catabolism of aggrecan by explant cultures of bovine articular cartilage maintained in the presence of retinoic acid. DESIGN: The kinetics of loss of 35S-labeled and total aggrecan from explant cultures of bovine articular cartilage maintained in the presence of 1 micro M retinoic acid and exposed to varying concentrations of glucosamine or mannosamine was investigated over a 9-day culture period. In other experiments, the reversibility of the inhibition of aggrecan catabolism by glucosamine or mannosamine was investigated in cultures exposed to these amino sugars for the first 5 days of a 15-day culture period. The metabolism of chondrocytes exposed to these amino sugars was evaluated by measurement of lactate production or 3H-serine and 35S-sulfate incorporation into protein and glycosaminoglycans, respectively. The direct effect of these amino sugars on soluble aggrecanase activity was determined from immunoblots of aggrecan digests. RESULTS: Glucosamine at 5mM concentration and mannosamine at 2mM concentration inhibited degradation of radiolabeled and chemical levels of aggrecan. At concentrations of up to 10mM amino sugars, the metabolism of chondrocytes was not impaired, as determined by lactate production, protein synthesis and the incorporation of 35S-sulfate into proteoglycans. These amino sugars did not inhibit soluble aggrecanase activity. The exposure of articular cartilage explants to 5mM glucosamine or mannosamine for 5 days in culture in the presence or absence of retinoic acid did not provide long-term suppression of stimulated aggrecan loss. CONCLUSIONS: This study indicates that continuous presence of amino sugars is required to protect cartilage from stimulated loss of aggrecan.

Aggrecans↗
PubMed1991

Radiographic grading of the severity of knee osteoarthritis: relation of the Kellgren and Lawrence grade to a grade based on joint space narrowing, and correlation with arthroscopic evidence of articular cartilage degeneration.

We examined standing knee radiographs of 92 patients who had chronic knee pain and radiographic evidence of mild or moderate osteoarthritis (OA) according to the Kellgren and Lawrence (K/L) criteria. Because the K/L criteria overemphasize osteophytosis relative to joint space narrowing (JSN), we graded OA severity also with a scoring system that placed greater emphasis on JSN than on osteophytes. In each case, the articular cartilage was visualized directly at arthroscopy. Of 17 patients whose radiographic findings were normal by both the K/L criteria and our JSN-weighted criteria, 7 had advanced tibiofemoral and/or patellofemoral compartment changes of OA seen at arthroscopy, emphasizing the insensitivity of the radiograph for detecting early articular cartilage loss. In addition, tibiofemoral JSN was common in the presence of normal articular cartilage. The JSN-weighted scale provided no advantage over the K/L criteria for assessing the severity of articular cartilage changes of OA.

Adult↗
PubMed2001

Age-related changes in the synthesis and mRNA expression of decorin and aggrecan in human meniscus and articular cartilage.

OBJECTIVE: To determine if the biosynthesis of aggrecan and decorin in the human meniscus and the potential of the cells to express these macromolecules (mRNA), is affected by the age of the individual and that if any changes are observed are they different to those measured in articular cartilage obtained from the same joint. DESIGN: Radiolabelling of tissue explants, anion-exchange chromatography and agarose-polyacrylamide gel electrophoresis were used to analyze newly synthesized proteoglycans. A quantitative, competitive reverse-transcriptase polymerase chain reaction was developed and applied to the tissue to measure the expression of decorin and aggrecan mRNA. RESULTS: Proteoglycan synthesis in the meniscus was higher in young donors (1-5 mmoles sulfate incorporated/h/mgDNA, under 20 years of age) than in adult tissues (0.5-1 mmoles incorporated/h/mgDNA, 20-62 years of age) and decorin was the major proteoglycan synthesized at this time. An age-related increase in the proportion of aggrecan synthesis in the meniscus was also observed using agarose-polyacrylamide gel electrophoresis. Both decorin (five-fold) and aggrecan (eight-fold) mRNA expression increased with age in meniscus whereas levels were relatively constant in articular cartilage. In addition, the synthesis of decorin and aggrecan and the expression of their mRNA was different in meniscus and articular cartilage from the same knee joint. CONCLUSION: The synthesis and turnover of aggrecan and decorin in the human meniscus is influenced by the age of the individual and is not the same as that observed for articular cartilage.

Adolescent↗
PubMedDate not supplied

Changes in the lipids of human articular cartilage with age.

Histochemical and chemical studies demonstrated a significant increase in the lipods of articular cartilage with advancing age. Triglycerides, cholesterol, and phospholipids were identified chemically and were shown by comparative staining procedures to be present in intracellular and extracellular lipids. The distribution and the composition of the extracellular lipids were interpreted as indicating that the extracellular lipids are of cellular origin. Glycolipids were extracted from cartilage of all ages and were shown to account for a portion of the increase in total lipid with age. Glycolipids extracted from aged cartilage were partially characterized. Cerebrosides, sulfatides, and gangliosides were detected. Glycolipids were estimated to comprise from 5 to 10% of the total lipid of articular cartilage. Arachidonic acid concentrations increased maredly with age in the surface of cartilage but were present in trace amounts in deep cartilage, demonstrating clear-cut differences in the levels as well as the location of this fatty acid precursor of the prostaglandins (PGE2 and PGF2alpha).

Adolescent↗
PubMed2003

Alterations in endogenous osteogenic protein-1 with degeneration of human articular cartilage.

A synchronized balance between synthesis and breakdown of extracellular matrix (ECM) molecules in normal articular cartilage is disturbed in osteoarthritis (OA). The focus of our study is the anabolic factor, osteogenic protein-1 (OP-1) that is expressed in articular cartilage and is able to induce the synthesis of ECM components. The major aim was to investigate both qualitatively and quantitatively endogenous OP-1 in normal, degenerative, and OA cartilage. Normal and degenerative cartilage was obtained at autopsies from femoral condyles of human organ donors with no documented history of joint disease; OA cartilage was obtained from patients undergoing joint arthroplasty. Appearance of donor cartilage was evaluated by Collins scale, where normal cartilage is assigned grades 0-1, and degenerated cartilage is assigned grades 2-4. OP-1 mRNA expression was assessed by RT-PCR; OP-1 protein (pro- and active forms) was qualitatively analyzed by Western blotting and quantified by OP-1 ELISA. The highest levels of OP-1 expression (mRNA and protein) were detected in normal cartilage of grade 0. The concentration of OP-1 protein was about 50 ng per gram cartilage dry weight. With the progression of cartilage degeneration (increased Collins grades and OA) OP-1 protein was down-regulated up to 9-fold. These changes affected primarily the active form of OP-1. OP-1 message also declined in cartilages with the increase of degenerative changes. In conclusion, an overall decrease in endogenous OP-1 in degenerated and OA tissue suggests that OP-1 could be one of the factors responsible for normal homeostasis and matrix integrity in cartilage.

Adult↗
PubMed2004

Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal cells derived from bone marrow.

OBJECTIVE: Cartilage-derived morphogenetic protein 1 (CDMP1), which is a member of the transforming growth factor-beta superfamily, is an essential molecule for the aggregation of mesenchymal cells and acceleration of chondrocyte differentiation. In this study, we investigated whether CDMP1-transfected autologous bone marrow-derived mesenchymal cells (BMMCs) enhance in vivo cartilage repair in a rabbit model. METHODS: BMMCs, which had a fibroblastic morphology and pluripotency for differentiation, were isolated from bone marrow of the tibia of rabbits, grown in monolayer culture, and transfected with the CDMP1 gene or a control gene (GFP) by the lipofection method. The autologous cells were then implanted into full-thickness articular cartilage defects in the knee joints of each rabbit. RESULTS: During in vivo repair of full-thickness articular cartilage defects, cartilage regeneration was enhanced by the implantation of CDMP1-transfected autologous BMMCs. The defects were filled by hyaline cartilage and the deeper zone showed remodelling to subchondral bone over time. The repair and reconstitution of zones of hyaline articular cartilage was superior to simple BMMC implantation. The histological score of the CDMP1-transfected BMMC group was significantly better than those of the control BMMC group and the empty control group. CONCLUSION: Modulation of BMMCs by factors such as CDMP1 allows enhanced repair and remodelling compatible with hyaline articular cartilage.

Animals↗
PubMed1998

Expression and activity of articular cartilage hyaluronidases.

The glycosaminoglycan hyaluronan is an important component of the extracellular matrix of articular cartilage, contributing to both the structural and functional integrity of this highly specialized tissue. Hyaluronan is known to be synthesized and turned over by the resident chondrocytes, although the mechanisms involved in hyaluronan degradation are not precisely defined. Recently, the cDNA sequences of extracellular hyaluronidases present on spermatazoa and in human serum have been reported, and we have utilized these data to investigate the expression and activity of these and/or related enzymes by articular cartilage chondrocytes. By using "gene-homology" RT-PCR techniques, three hyaluronidase isozymes were found to be expressed by chondrocytes, and hyaluronidase activity was detected in cell membrane extracts and conditioned media from chondrocyte monolayer cultures following acidification to pH 4.5 or pH 3.7. In addition, the levels of mRNA for two of the chondrocyte hyaluronidases were upregulated by IL-1 and TNF stimulation, thereby implicating cartilage-derived hyaluronidase activity as a factor contributing to cytokine-induced extracellular matrix degradation during synovial joint disease.

Aged↗
PubMed2000

The chondrocyte cytoskeleton in mature articular cartilage: structure and distribution of actin, tubulin, and vimentin filaments.

We investigated the structure of the chondrocyte cytoskeleton in intact tissue sections of mature bovine articular cartilage using confocal fluorescence microscopy complemented by protein extraction and immunoblotting analysis. Actin microfilaments were present inside the cell membrane as a predominantly cortical structure. Vimentin and tubulin spanned the cytoplasm from cell to nuclear membrane, the vimentin network appearing finer compared to tubulin. These cytoskeletal structures were present in chondrocytes from all depth zones of the articular cartilage. However, staining intensity varied from zone to zone, usually showing more intense staining for the filament systems at the articular surface compared to the deeper zones. These results obtained on fluorescently labeled sections were also corroborated by protein contents extracted and observed by immunoblotting. The observed cytoskeletal structures are compatible with some of the proposed cellular functions of these systems and support possible microenvironmental regulation of the cytoskeleton, including that due to physical forces from load-bearing, which are known to vary through the depth layers of articular cartilage.

Actins↗
PubMed2000

Neochondrogenesis in repair of full-thickness articular cartilage defects using free autogenous periosteal grafts in the rabbit. A follow-up in six months.

OBJECTIVE: To analyse the repair of lesions of articular cartilage with periosteum-free implants and follow-up at 6 months. DESIGN: Thirty-six New Zealand rabbits, 4-6 weeks old, were used. Full-thickness articular cartilage defects in the medial femoral condyle were created. Spontaneous evolution occurred in 18 animals; the other 18 animals were treated with a free autogenous periosteal tibial implant fixed with Tissucol. Animals were killed in groups of six at 8, 12 and 24 weeks. Macroscopic, histologic and histochemical results were evaluated and analysed statistically using the Mann-Whitney U-test. RESULTS: The spontaneous evolution of the lesion did not lead to complete repair in any case. The periosteum-free implant provided complete repair of the lesion and statistically significant restoration of the articular surface. CONCLUSIONS: In the rabbit, this study confirms the incomplete spontaneous repair of articular cartilage and the chondrogenic potential of tibial periosteum-free implants, with long-term maintenance of the macroscopic, histologic and histochemical characteristics of neo-cartilage. This raises the possibility of its use as an alternative method in the repair of circumscribed osteochondral lesions in young patients.

Animals↗
PubMed1985

Autoantibody specificities of immune complexes sequestered in articular cartilage of patients with rheumatoid arthritis and osteoarthritis.

To define autoantibody specificities of immune complexes sequestered in articular cartilage of patients with rheumatoid arthritis and osteoarthritis, extracts were obtained from articular cartilage specimens from 16 patients with rheumatoid arthritis, 11 patients with osteoarthritis, and 6 normal controls. Radioimmunoassays of the extracts revealed that rheumatoid cartilage contained 37 times more IgM and 14 times more IgG than did normal cartilage extracts. In addition, osteoarthritic cartilage contained 3 times more IgM and IgG than the normal tissues. IgM rheumatoid factor was found in 13 of 16 rheumatoid cartilage extracts but in none of 11 osteoarthritic or 6 normal control extracts. IgG rheumatoid factor was detected in 4 of 7 seropositive rheumatoid but in none of 5 osteoarthritic cartilage extracts. More than 60% of the rheumatoid cartilage extracts were positive for native and denatured collagen II antibodies. Surprisingly, 50% of the osteoarthritic specimens also contained significant titers of collagen antibodies. Similar results were obtained with osteoarthritic menisci extracts. These findings indicate that the immune complexes sequestered in rheumatoid cartilage contain autoantibodies that are probably synthesized locally by cells infiltrating the inflamed synovium. If immune complexes trapped in cartilage play an important role in cartilage damage, our findings would provide a possible pathogenic mechanism that explains the self-perpetuating and chronic nature of cartilage degradation in rheumatoid arthritis and osteoarthritis.

Adult↗
PubMed2006

Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation.

OBJECTIVE: To investigate how the time of initiation influences the effects of estrogen therapy on type II collagen (CII) turnover and the structural integrity of articular cartilage in ovariectomized rats and to determine whether estrogen exerts direct effects on the catabolic function of chondrocytes ex vivo. METHODS: A total of 46 Sprague-Dawley rats were distributed into 1 of the following treatment groups: 1) ovariectomy, 2) ovariectomy plus early estrogen therapy, 3) ovariectomy plus delayed estrogen therapy, or 4) sham operation. Cartilage turnover was estimated by measuring the serum levels of C-telopeptide of type II collagen (CTX-II). Cartilage lesions at week 9 were quantified using a published scoring technique. The presence of the CTX-II epitope in articular cartilage was assessed by immunohistochemistry. The effects of estrogen (1-100 nM) on chondrocytes were investigated in bovine cartilage explants subjected to catabolic cytokines (tumor necrosis factor alpha [TNFalpha] and oncostatin M [OSM]). RESULTS: In ovariectomized rats, estrogen therapy evoked significant decreases in serum CTX-II independently of the time of initiation; yet, delayed initiation resulted in diminished efficacy in terms of preventing cartilage lesions. CTX-II fragments were present in articular cartilage, colocalizing with early lesions at the cartilage surface. In untreated animals, the early relative increases in serum CTX-II were proportional to the severity of cartilage lesions at week 9 (r = 0.73, P < 0.01). Estrogen significantly and dose-dependently countered CTX-II release from TNFalpha plus OSM-stimulated cartilage explants ex vivo. CONCLUSION: Our results suggest that estrogen counters the acceleration of CII degradation and related structural alterations, and these benefits can be maximized by early initiation after menopause. The protective effect of estrogen seems to involve direct inhibition of the catabolic function of chondrocytes.

Animals↗
PubMed1999

Complement C1s activation in degenerating articular cartilage of rheumatoid arthritis patients: immunohistochemical studies with an active form specific antibody.

OBJECTIVE: The first complement component C1s was reported to have novel functions to degrade matrix components, besides its activities in the classic complement pathway. This study explores participation of C1s in articular cartilage degradation in rheumatoid arthritis (RA). METHODS: Normal articular cartilage (n = 6) and cartilage obtained from joints with RA (n = 15) and osteoarthritis (OA, n = 10) were immunostained using anti-C1s monoclonal antibodies PG11, which recognises both active and inactive C1s, and M241, which is specifically reactive to activated C1s. The effects of inflammatory cytokines on C1s production by human articular chondrocytes were also examined by sandwich ELISA. RESULTS: In normal articular cartilage, C1s was negative in staining with both PG11 and M241. In contrast, degenerating cartilage of RA was stained with PG11 (14 of 15 cases), and in most of the cases (13 of 15 cases) C1s was activated as revealed by M241 staining. In OA, C1s staining was restricted in severely degrading part of cartilage (5 of 10 cases), and even in that part C1s was not activated. In addition, C1s production by chondrocytes in vitro was increased by an inflammatory cytokine, tumour necrosis factor alpha. CONCLUSION: These results suggest that C1s activated in degenerative cartilage matrix of RA but not in that of OA. C1s is thought to participate in the pathogenesis of RA through its collagenolytic activity in addition to the role in the classic cascade.

Adolescent↗