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Biomedical subjects

K Mikecz

Publications and source records attributed to K Mikecz.

At least 37 records · Page 2Linked to original sources
PubMed1999

Modulation of hyaluronan receptor (CD44) function in vivo in a murine model of rheumatoid arthritis.

OBJECTIVE: To determine how in vivo modulation of CD44 function by antibodies influences disease severity in a murine model of rheumatoid arthritis. METHODS: Mice with proteoglycan (PG)-induced arthritis were subjected to systemic treatment with 3 different monoclonal antibodies against CD44. Joint swelling and serum levels of hyaluronan (HA) and soluble CD44 (sCD44) were monitored. Inflammatory leukocyte infiltration in the joints, cell surface CD44 expression, and leukocyte adhesion to HA were compared. The effects of anti-CD44 treatment on the immune status of arthritic animals were also determined. RESULTS: Antibody IRAWB14, which enhances HA binding, aggravated the inflammatory symptoms, while KM201, which blocks ligand binding, reduced the severity of arthritis. The most effective suppression of inflammation was noted upon treatment with antibody IM7, whose epitope lies outside the HA binding domain of CD44. Serum levels of sCD44 increased, and HA levels decreased, in response to IM7. KM201 and IM7 treatment reduced, but IRAWB14 treatment enhanced, the adhesion of leukocytes to HA. However, these antibodies had little effect on PG-specific immune responses. CONCLUSION: Each antibody acted in vivo by virtue of its combined effects on CD44-HA binding and CD44 shedding. The dramatic reduction in arthritis severity effected by IM7 treatment was associated with extensive shedding of cell surface CD44 molecules. Loss of CD44 appears to be a major factor in preventing CD44- and HA-dependent cell-matrix interactions at the inflammatory site. Our study indicates a critical role for CD44 in the pathology of joint inflammation and reveals a unique mechanism of receptor down-regulation, which can be used therapeutically.

Animals↗
PubMed1999

Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis.

OBJECTIVE: Proteoglycan-induced arthritis (PGIA) is a murine model of rheumatoid arthritis (RA), both in terms of its pathology and its genetics. PGIA can only be induced in susceptible murine strains and their F2 progeny. As with RA, the genetics are complex, containing both major histocompatibility complex (MHC)-related and non-MHC-related components. Our goal was to identify the underlying non-MHC-related loci that confer PGIA susceptibility. METHODS: We used 106 polymorphic markers to perform simple sequence-length polymorphism analysis on F2 hybrids of susceptible (BALB/c) and nonsusceptible (DBA/2) strains of mice. Because both strains of mice share the H2d haplotype, this cross permits identification and analysis of non-MHC-related genes. RESULTS: We identified a total of 12 separate quantitative trait loci (QTL) associated with PGIA, which we have named Pgia1 through Pgia12. QTLs associated with the inflammatory symptoms of PGIA were linked to chromosomes 7, 9, 15 (2 separate loci), 16, and 19. QTLs associated with autoantibody production were identified on chromosomes 1, 2, 7, 8, 10, 11, 16, and 18. QTLs on chromosomes 7 and 16 showed linkage to both inflammation and autoantibody production, suggesting a shared regulatory component in arthritis induction. The first inflammation QTL on chromosome 15 and the autoantibody QTL on chromosome 7 originate from the DBA/2 background, which indicates that as in RA, susceptibility genes can originate from heterogeneous backgrounds. CONCLUSION: These data demonstrate the complexity of PGIA, where QTLs may be involved in multiple traits or even originate from a genetic background previously determined to be resistant.

Animals↗
PubMed1998

Critical roles of glycosaminoglycan side chains of cartilage proteoglycan (aggrecan) in antigen recognition and presentation.

Systemic immunization of BALB/c mice with proteoglycan (aggrecan) from fetal human cartilage induces progressive polyarthritis, an experimental disease similar to human rheumatoid arthritis. The development of the disease in this genetically susceptible murine strain is based on cross-reactive immune responses between the immunizing fetal human and mouse self-proteoglycans. One of the cross-reactive and arthritogenic T cell epitopes (92GR/QVRVNSA/IY) is localized in the G1 domain of human/murine proteoglycan. Susceptible BALB/c mice, however, develop arthritis only if both the chondroitin sulfate (CS) and keratan sulfate (KS) side chains of the arthritogenic human proteoglycans are removed. The function of these two glycosaminoglycan side chains is opposite. The presence of a KS side chain in adult proteoglycan inhibits the recognition of arthritogenic T cell epitopes, prevents the development of T cell response, and protects animals from autoimmune arthritis. In contrast, the depletion of the CS side chain generates clusters of CS stubs and provokes a strong B cell response. These carbohydrate-specific B cells are the most important proteoglycan APC. Taken together, proteoglycan-induced progressive polyarthritis is dictated by three major components: genetic background of the BALB/c strain, highly specific T cell response to epitope(s) masked by a KS chain in aging tissue, and the presence of proteoglycan (CS stub)-specific B cells required for sufficient Ag presentation.

Adolescent↗
PubMed1998

Progressive polyarthritis induced in BALB/c mice by aggrecan from normal and osteoarthritic human cartilage.

OBJECTIVE: To find an "unlimited" source of antigenic material (aggrecan) for arthritis induction in BALB/c mice; to analyze the specificities of immune reactions to aggrecan and type II collagen in 2 arthritis-susceptible murine strains, BALB/c mice for proteoglycan (aggrecan)-induced arthritis and DBA/1j mice for collagen-induced arthritis; to compare the histopathologic features of arthritis induced by purified aggrecans or total extracts of osteoarthritic (OA) cartilage; and to determine arthritis susceptibility in various BALB/c colonies. METHODS: Aggrecans from total extracts of human fetal, normal adult, OA, and rheumatoid cartilage samples and from osteophytes were isolated, purified by gradient centrifugation, deglycosylated, characterized, and tested for arthritis induction. Purified type II collagen and salt-soluble collagens from OA cartilage were denatured, stromelysin treated, and used for immunization and arthritis induction in arthritis-susceptible (DBA/1j and BALB/c) murine strains. RESULTS: Chondrocytes from OA cartilage synthesize predominantly fetal-type aggrecan, which is the most efficient antigenic material for arthritis induction in BALB/c mice. The critical autoimmune/arthritogenic T cell epitopes of aggrecan are located in the G1 domain. Although most of the aggrecan molecules are heavily degraded and lost from OA cartilage, the G1 domain-containing fragments accumulate in OA cartilage. The amount of G1-containing fragments is approximately twice as much in OA than in normal adult articular cartilage, and the arthritogenic epitope(s) remains intact in G1-containing fragments retained in cartilage. Thus, total extracts of OA cartilage (without additional purification), if deglycosylated appropriately, can be used as arthritogenic material in BALB/c mice. CONCLUSION: Predominantly G1 domain-containing fragments of aggrecan accumulate in OA cartilage, and these are the fragments which induce arthritis in BALB/c mice. Arthritis induction is highly specific for aggrecan epitopes and dictated by the genetic background of the BALB/c strain.

Adult↗
PubMed1997

CD44 expression by leucocytes in rheumatoid arthritis and modulation by specific antibody: implications for lymphocyte adhesion to endothelial cells and synoviocytes in vitro.

Anti-CD44 MoAb IM7 induced the loss of CD44 from mouse leucocytes thereby inhibiting leucocyte migration and joint inflammation in murine arthritis. Thus, targeting CD44 with MoAb may have potential for the treatment of patients with inflammatory joint diseases. Expression of CD44 by peripheral blood (PB) and synovial fluid (SF) leucocytes from rheumatoid arthritis (RA) patients was compared and the ability of IM7 to modulate this expression determined. RASF lymphocytes showed increased CD44 expression compared with those in PB indicative of an activated phenotype. As inflammatory SF did not up-regulate CD44 expression on PB lymphocytes, the increased CD44 expression by SF lymphocytes was a result of the selective homing of CD44(high) cells to the synovium rather than an effect of the synovial environment. RASF granulocytes showed reduced CD44 expression compared with those in PB, again indicative of an activated phenotype. However, this reduction could be induced on PB granulocytes following culture with inflammatory SF and was inhibited by anti-TNF-alpha MoAb, implying that soluble factors in inflammatory SF such as TNF-alpha induced granulocyte activation and CD44 loss. IM7 induced the loss of CD44 from lymphocytes (both from PB and SF) and granulocytes in vitro, but was subsequently re-expressed after 24 h culture in the absence of the MoAb. This loss of CD44 was blocked by serine- and metalloprotease inhibitors implying that IM7 induced the proteolytic cleavage of CD44 by a mechanism similar to that reported for the loss of CD44 from PMA-activated granulocytes. Furthermore, IM7-treated CD44(low) lymphocytes showed reduced adherence to both an endothelial cell line and RA synovial fibroblasts in vitro. The unique ability of IM7 to reduce CD44 expression by lymphocytes suggests that it could prevent lymphocyte extravasation and synovial infiltration in RA as previously reported in murine arthritis.

Antibodies, Monoclonal↗
PubMed1996

Chondrocyte matrix metalloproteinase-8. Human articular chondrocytes express neutrophil collagenase.

This study confirms that normal human articular chondrocytes express neutrophil collagenase or matrix metalloproteinase-8 (MMP-8), a gene product previously thought to be expressed exclusively by neutrophil leukocytes. Both MMP-8 protein and mRNA were present in articular cartilages collected from normal human donors. Cartilage extracts were assayed by immunoblotting and by analysis of enzymatic activity on gelatin-substrate gels. Latent MMP-8 extracted from cartilage has a molecular mass of 55 kDa; active MMP-8 was identified at 46 and 42 kDa. In the absence of a reducing agent, MMP-8 migrated in a high molecular mass complex above 200 kDa. Northern blotting results demonstrated the expression of MMP-8 in chondrocytes, which could be up-regulated by stimulation with interleukin-1 beta. In addition, reverse transcription-polymerase chain reaction using nested primers and in situ hybridization revealed the presence of MMP-8 mRNA in chondrocytes. The presence of both MMP-8 protein and message in cartilage supports the concept that neutrophil collagenase could be the enzyme described as "aggrecanase".

Blotting, Northern↗
PubMed1996

Chondrocyte matrix metalloproteinase-8: up-regulation of neutrophil collagenase by interleukin-1 beta in human cartilage from knee and ankle joints.

The loss of aggrecan from articular cartilage may lead to the development of osteoarthritis (OA). Degradation products of human aggrecan, generated in vivo by enzymatic cleavages, have been identified in synovial fluid of patients with rheumatoid arthritis and OA. One matrix metalloproteinase (MMP), stromelysin (MMP-3), and an unidentified proteinase called "aggrecanase" are believed to generate these products in pathologic conditions. Thus far, only one proteinase, neutrophil collagenase (MMP-8), has been shown in vitro to be capable of cleavage of the aggrecan molecule at the "aggrecanase" site. In this study, we compare the presence and distribution of MMP-3 and MMP-8 in cartilages from two different joints of normal human donors. We determined whether mRNA for MMP-8 is expressed in normal human articular cartilage from different joints. In addition, we compared differences in MMP-8 and MMP-3 gene expression between human ankle and knee cartilage after in vitro stimulation by interleukin (IL)-1 beta. These two joints were chosen because the incidence of symptomatic and radiographic OA varies between the different joints. The knee is the most frequently involved joint, whereas the ankle (talocrural) joint is relatively rarely affected. Message for MMP-8 was detected in untreated cartilage from normal knee joints, but not in untreated cartilage of normal ankle joints. Message for MMP-3 was detectable in most of the knee and ankle cartilages. Messenger RNA expression for both MMPs could be up-regulated by IL-1 beta. The highest doses of IL-1 beta appeared to be most effective in stimulation of mRNA for MMP-3, whereas MMP-8 expression was more sensitive to lower doses of IL-1 beta. The fact that ankle cartilage with a low incidence of OA does not express MMP-8, whereas knee cartilage with a high incidence of OA does not express MMP-8, whereas knee cartilage with a high incidence of OA does constitutively express MMP-8, suggests that MMP-8 might be one of the key enzymes in the pathogenesis of osteoarthritis. This is further supported by our finding that the earliest signs of cartilage degradation were very similar to those found in IL-1 beta-treated explants.

Adolescent↗
PubMed1995

A proteoglycan (aggrecan)-specific T cell hybridoma induces arthritis in BALB/c mice.

Aggrecan, the high buoyant density cartilage proteoglycan (PG), has been shown to induce progressive polyarthritis and ankylosing spondylitis in genetically susceptible BALB/c mice. To further characterize the nature of the autopathogenic effector T cells operating in these mice and to determine the region(s) of the PG molecule recognized by these T cells, we generated PG-specific T cell hybridomas from arthritic mice. One of the PG-specific T cell hybridomas (5/4E8), when injected into naive irradiated BALB/c mice, was capable of inducing clinical and histopathologic signs of arthritis. Massive swelling and redness of the paws dominated the clinical picture. A reactive synovial cell proliferation, the accumulation of hybridoma and inflammatory cells in the enlarged joint space, the loss of PG from the superficial layer of the articular cartilage, and the erosion of articular surface were identical histopathologic signs to those found either in primary or adoptive transfer of PG-induced arthritis. The PG-specific and arthritogenic T cell hybridoma (5/4E8) expressed TCR-alpha beta + (V beta 4), CD4+, and CD8- phenotypes and belonged to the Th1 subset, as the cells secreted IL-2 and IFN-gamma, but not IL-4 upon PG stimulation, and the response was MHC class II (I-Ad)-restricted. These observations provide direct evidence that PG-specific Th cells play crucial roles in autoimmune arthritic processes.

Aggrecans↗
PubMed1995

The potential role of fibroblasts in periprosthetic osteolysis: fibroblast response to titanium particles.

Periprosthetic osteolysis with or without aseptic loosening is a major clinical problem in total hip arthroplasty. While the macrophage response to prosthetic wear debris and its role in periprosthetic osteolysis has been extensively studied, information regarding other cell types (fibroblasts, osteoblasts) is limited. This study explored the response of fibroblasts to particulate wear debris. Fibroblasts isolated from interfacial membranes of patients with failed total hip replacements and normal synovial tissue, when challenged with small-sized ( < 3 microns) titanium (Ti) particles, responded with significantly enhanced expressions of collagenase, stromelysin and, to a much lesser extent, their tissue inhibitor of metalloproteinases (TIMP). These "regulated" expressions at both mRNA and protein levels were correlated with the size and composition of particles. De novo protein synthesis was required for the regulation of these mRNAs. A similar effect could be induced by the treatment of the cells with particle-free conditioned medium from Ti particle-stimulated fibroblasts. Furthermore, this conditioned medium significantly suppressed the mRNA levels of procollagen alpha 1 (I) and alpha 1 (III) in osteoblast-like MG-63 cells. It is concluded that fibroblasts stimulated with certain particle debris may play an important role in periprosthetic osteolysis by releasing bone-resorbing metalloproteinases and mediator(s) which resulted in suppressed collagen synthesis in osteoblasts.

Base Sequence↗
PubMed1995

Interferon-gamma but not granulocyte/macrophage colony-stimulating factor augments proteoglycan presentation by synovial cells and chondrocytes to an autopathogenic T cell hybridoma.

Immunization of BALB/c mice with human cartilage proteoglycan (aggrecan) produces a progressive polyarthritis, similar in many aspects to human rheumatoid arthritis, and autoreactive T cells are necessary for initiation of the disease. To study the immunopathological mechanisms operating in the synovium of arthritic mice, we isolated a proteoglycan (PG)-specific arthritogenic T-cell hybridoma, 5/4E8, and examined the presentation of PG to this T-cell hybridoma by mouse synovial cells and chondrocytes. Both cell types expressed very low levels of major histocompatibility complex (MHC) class II following isolation and culture and were unable to present PG to the hybridoma. However, following stimulation with interferon-gamma (IFN-gamma), both synovial cells and chondrocytes showed a marked increase in MHC class II expression and consequently were able to present PG very effectively. The PG-specific responses of the hybridoma were abrogated by an anti-Ia monoclonal antibody. Granulocyte-macrophage colony-stimulating factor (GM-CSF), one of the most abundant cytokines in the rheumatoid synovium, had no effect on the antigen-presenting capacity of synovial cells and chondrocytes, either on its own or together with IFN gamma.

Aggrecans↗
PubMed1995

Anti-CD44 treatment abrogates tissue oedema and leukocyte infiltration in murine arthritis.

A ubiquitous cell adhesion receptor, CD44, preferentially binds hyaluronan, a polysaccharide macromolecule that is present in most extracellular matrices. Hyaluronan molecules have large hydrodynamic volumes that entrap substantial amounts of water and can therefore control tissue hydration (swelling). CD44 is overexpressed by synovial cells and leukocytes, and hyaluronan is overproduced in the rheumatoid synovium and in other inflammatory sites. Nevertheless, the role of the CD44-hyaluronan interaction during inflammation is unclear. Our evidence shows that the CD44 receptor plays a critical role in governing the migration of inflammatory leukocytes into the extravascular compartment of the synovium in murine arthritis. An anti-CD44 antibody induces a rapid loss of CD44 from both leukocytes and synovial cells and displays an inhibitory effect on cell-extracellular matrix interactions in the synovium. As a result, the administration of such an antibody abrogates tissue swelling and leukocyte infiltration, two major components of inflammation.

Amino Acid Sequence↗
PubMed1995

Antigen-specific B cells present cartilage proteoglycan (aggrecan) to an autoreactive T cell hybridoma derived from a mouse with proteoglycan-induced arthritis.

Cartilage proteoglycan (aggrecan)-induced polyarthritis in BALB/c mice is characterized by chronic inflammation and destruction of joint tissues similar to that observed in human rheumatoid arthritis. The immunization of mice with fetal human proteoglycan (PG) elicits specific antibodies to the immunizing antigen of which a population cross-reacts with native mouse PG. This (auto)antibody production is immediately followed by an explosive proliferation of autoreactive T cells, suggesting that PG-specific B cells may participate in antigen presentation of PG to autoreactive T cells. We therefore isolated B cells from the spleens and lymph nodes of PG-immunized mice and examined their ability to present PG to a PG-specific T cell hybridoma. The antigen-specific T cell responses elicited by B cells from PG-immunized mice (both arthritic and clinically asymptomatic) were markedly higher than those of non-immune mice and keyhole limpet haemocyanin (KLH)-immunized mice, and these B cells could present low PG concentrations. Levels of B cell presentation corresponded with the serum levels of PG-specific antibodies, implying that these B cells were presenting the PG specifically via their surface immunoglobulin. This B cell-T cell interaction was strongly dependent on MHC class II/T cell receptor (TCR), LFA-1/intercellular adhesion molecule-1 (ICAM-1) and CD28/B7 interactions, as antibodies to Ia, ICAM-1 and B7-2 (but not to B7-1) markedly reduced presentation. These data indicate that PG-specific B cells may play an essential role in governing the development of PG-induced arthritis.

Aggrecans↗
PubMed1995

Presentation of cartilage proteoglycan to a T cell hybridoma derived from a mouse with proteoglycan-induced arthritis.

Immunization of BALB/c mice with human fetal cartilage proteoglycan (PG) produces progressive polyarthritis, and T cells play key roles in the development of the disease. To gain an understanding of how PG is presented to autoreactive T cells by synovial antigen-presenting cells (APC), we examined the abilities of various syngeneic APC in presenting PG to a specific T cell hybridoma 5/4E8, derived from a mouse with PG-induced arthritis. A20 B lymphoma cells and spleen cells were strong presenters of PG, but synoviocytes and P388D1 macrophages could only present PG effectively after stimulation with interferon-gamma (IFN-gamma). The IFN-gamma exerted its effect by up-regulating both MHC class II and intercellular adhesion molecule-1 (ICAM-1) expression by these cells as neutralizing antibodies to Ia, LFA-1 and ICAM-1 inhibited presentation. Our studies also showed that synoviocytes and spleen cells took up and processed PG more rapidly than the cell lines. Cysteine and serine protease-dependent antigen presentation of PG was blocked at 4 degrees C, 18 degrees C and by chloroquine treatment, indicating that presentation required active uptake and processing in an acidic compartment, probably in lysosomes. Also, keratan sulphate-depleted and cyanogen bromide (CNBr) and 2-nitro-5-thiocyanobenzoic acid (NTCB)-cleaved PG elicited stronger T cell responses, as they were more easily processed than the native molecule. Furthermore, CNBr-generated peptides were presented by fixed APC, indicating that core protein fragments of cartilage PG can be presented directly by APC in context with MHC class II molecules.

Animals↗
PubMed1995

Mapping of arthritogenic/autoimmune epitopes of cartilage aggrecans in proteoglycan-induced arthritis.

Immunization of BALB/c mice with chondroitin sulfate-depleted proteoglycan (aggrecan) of fetal human cartilage produces progressive polyarthritis and ankylosing spondylitis. The development of the disease in genetically susceptible BALB/c mice is dependent upon the expression of both cell-mediated and humoral immune responses against the host mouse cartilage proteoglycan (PG). Although cartilage PGs from various species have many biochemical and immunological similarities, only a select group of PGs from fetal and newborn human, fetal pig and canine articular cartilages, human osteophytes and human chondrosarcomas are able to induce arthritis in BALB/c mice. Arthritis develops only in mice that also develop autoantibodies to self-cartilage PGs, although autoantibodies occasionally are present in non-arthritic animals as well. The protease-sensitive auto/arthritogenic epitope(s) is located in, or close to, the chondroitin sulfate (CS) attachment region of the PG molecule. The primary structure of the core protein is responsible for the autoimmune/arthritogenic effect of this select group of PGs, whereas the core protein epitopes are masked by glycosaminoglycan (GAG)-side chains. The CS side chains seem to inhibit antigen recognition in all aggrecans with arthritogenic potential, whereas a similar effect with keratan sulfate (KS) appears only in PGs of aging cartilages.

Aggrecans↗
PubMed1994

Mediators and autopathogenic effector cells in proteoglycan-induced arthritic and clinically asymptomatic BALB/c mice.

Proteoglycan (aggrecan)-induced arthritis is an autoimmune inflammatory animal model produced in genetically susceptible BALB/c mice. This animal model shows many similarities to human rheumatoid arthritis as indicated by clinical assessments, histopathological studies, and immunological parameters. The systemic immunization of mice with a select group of cartilage proteoglycans provokes immune responses to the immunizing antigen and then the production of cross-reactive antibodies to self proteoglycans. This is followed by an explosive proliferation of autoreactive T cells, especially in joint draining lymph nodes, accompanied by local (joint) inflammatory events. In the current experiments we found that lymphocytes from arthritic, or potentially arthritic but yet clinically asymptomatic animals, produced more IL-2 than those T cells obtained from animals immunized with nonarthritogenic PGs. In addition, synoviocytes isolated from prearthritic or arthritic animals produced several-fold more interleukin-1 beta (IL-1 beta) than cells from normal animals. Flow cytometric analysis indicated an autoantigen (mouse PG)-specific selective proliferation of surface Ig+/CD45R+ cells in prearthritic stages followed by the proliferation of predominantly T helper (CD4+) cells during and after the development of arthritis.

Animals↗
PubMed1994

Migration and homing of lymphocytes to lymphoid and synovial tissues in proteoglycan-induced murine arthritis.

OBJECTIVE: To describe the migration and homing of labeled donor lymphocytes to the lymphoid organs and synovial tissues of host animals, during the development of cartilage proteoglycan (PG)-induced arthritis adoptively transferred to syngeneic BALB/c mice. METHODS: Lymphocytes from either nonarthritic or arthritic donor animals were labeled with either fluorescent or radioactive cell linkers (PKH-GL) and injected into syngeneic, immunosuppressed mice. The homing patterns of donor lymphocytes following the injection of labeled cells were studied by fluorescence microscopy and by measurement of radioactivity in tissue samples. RESULTS: Lymphocytes from arthritic donors retained their ability to transfer the disease after labeling. In the lymphoid organs, arthritic and nonarthritic donor lymphocytes exhibited similar homing patterns, although remarkable differences were found in the number of homing cells derived from nonarthritic and arthritic donors. However, labeled cells only from arthritic animals migrated to the synovial tissue of the recipient mice, and their appearance was associated with the onset of arthritis. CONCLUSION: Lymphocytes from mice with PG-induced arthritis, in contrast to lymphocytes from non-arthritic donors, exhibit preferential homing to the synovial tissue of the host. Adoptive transfer of arthritis is linked to the appearance of these cells in the synovium.

Animals↗
PubMed1993

Functional assessment of joint use in experimental inflammatory murine arthritis.

A select group of cartilage proteoglycans (fetal human, porcine, and canine articular cartilages and human osteophytes, all depleted of chondroitin sulfate) produces progressive polyarthritis and spondylitis in BALB/c mice. The development of the disease in this murine strain is dependent on the expression of both cell-mediated and humoral immunities to host mouse cartilage proteoglycan. Autoantibodies have been detected in sera of arthritis animals from the fifth to sixth week after immunization, and their appearance precedes the development of the first clinical symptoms by a few days in animals with passively transferred arthritis. In this preliminary experiment, we describe several functional tests and gait analyses in normal mice, in acutely and chronically arthritic mice, and in randomly selected mice with proteoglycan-induced and collagen-induced arthritis. The procedures revealed that changes in joint use and gait could predate by weeks the appearance of the first clinical symptoms (joint swelling, redness, and joint stiffness) of arthritis in mice. Moreover, abnormalities measured by functional tests, such as strength of grip and maintenance of posture on sandpaper, wood, or vinyl surfaces at three different tilt angles (30, 45, and 60 degrees), and gait analysis preceded the appearance of autoantibodies in sera of immunized animals; this indicates that such measurements could provide a noninvasive and simple method to assess joint function accurately during the development of arthritis.

Animals↗