Extra-articular cartilage affected in collagen-induced, but not pristane-induced, arthritis models.

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting cartilaginous joints but also extra-articular tissues such as the nose and upper respiratory tract. We have investigated extra-articular cartilage involvement in two commonly used animal models for RA, collagen-induced and pristane-induced arthritis, by immunizing rats with different susceptibility to disease (LEW.1 A, LEW.1F and DA rats). We found that nasal and tracheolaryngeal cartilage is affected in LEW.1 A and DA rats to varying degrees in collagen-induced arthritis but not in any strain in the pristane-induced model. Antibodies to matrilin-1, a cartilage-specific protein expressed mainly in tracheolaryngeal and nasal cartilage but not in joints, were positively associated with the presence of inflammation in nasal cartilage. In contrast, no antibody response to matrilin-1 could be detected in pristane-induced arthritis. In addition, nasal vaccination with collagen type II prior to immunization in DA rats significantly decreased the antibody response to matrilin-1 at day 56, but not at earlier time points, indicating a late protective effect on extra-articular cartilage. We conclude that pristane-induced arthritis is a joint-specific model whereas collagen-induced arthritis affect joints as well as extra-articular cartilage. Furthermore, collagen immunization induces an antibody response to matrilin-1.

The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis.

OBJECTIVE: Relapsing polychondritis (RP) is an inflammatory disease that mainly affects cartilage tissue in the auricle, nose, and lower respiratory tract. When tracheolaryngeal cartilage is involved, the disease is occasionally fatal. Matrilin 1 is a cartilage-specific protein most prominently expressed in tracheal cartilage, but not in joint cartilage. Immunization with the protein in rats and mice induces respiratory distress and nasal destruction, as seen in RP. We investigated the response to matrilin 1 and other cartilage proteins in sera from patients with RP, 4 additional groups of patients with other major connective tissue diseases, and healthy control subjects. METHODS: Sera were analyzed by enzyme-linked immunosorbent assay (ELISA) for antibody responses to matrilin 1, types II, IX, and XI collagen, and cartilage oligomeric matrix protein (COMP). Titers above the mean + 3SD of controls were considered positive. Specificity of matrilin 1 recognition was further investigated by the capacity of high-titer sera to block the binding of a matrilin 1-specific monoclonal antibody in inhibition ELISAs. In vivo reactivity and specificity were tested by injecting sera into neonatal mice, and antibody binding was detected by immunohistochemical staining. RESULTS: Serum antibodies from RP patients bound tracheolaryngeal and nasal cartilage in vivo and inhibited the binding of anti-matrilin 1-specific monoclonal antibodies. Thirteen of the 97 RP patients had increased titers of matrilin 1 antibody. Positive titers correlated with respiratory symptoms in 69% of the cases. Significant responses to type II collagen and COMP were also detected. CONCLUSION: Antibodies to matrilin 1 bind tracheolaryngeal cartilage in vivo and are correlated with an inflammatory attack on tracheolaryngeal cartilage that is often seen in RP.

IL-10-deficient B10.Q mice develop more severe collagen-induced arthritis, but are protected from arthritis induced with anti-type II collagen antibodies.

IL-10 is a pleiotropic cytokine with stimulatory and inhibitory properties, and is thought to have a protective role in rheumatoid arthritis and collagen-induced arthritis (CIA). In this study, we investigated how IL-10 deficiency affects CIA and anti-collagen type II (CII) Ab-transferred arthritis in C57BL/10.Q (B10.Q) mice. The B10.Q.IL-10(-/-) mice had an 8-cM 129/Ola fragment around the IL-10 gene. The mice were treated with antibiotics, appeared healthy, and had no colitis. T cells from IL-10(-/-) mice expressed similar levels of IFN-gamma, IL-2, and IL-4 after mitogen stimulation; however, macrophages showed a reduced TNF-alpha production compared with IL-10(+/-) littermates. IL-10(-/-) mice had an increased incidence, and a more severe CIA disease than the IL-10(+/-) littermates. To study the role of IL-10 in T cell tolerance, IL-10(-/-) were crossed into mice carrying the immunodominant epitope, CII(256-270), in cartilage (MMC) or in skin (TSC). Both IL-10(-/-) and IL-10(+/-) MMC and TSC mice were completely tolerized against CIA, indicating that lack of IL-10 in this context did not break tolerance. To investigate whether IL-10 was important in the effector phase of CIA, arthritis was induced with anti-CII Abs. Surprisingly, IL-10(-/-) were less susceptible to Ab-transferred arthritis, as only 30% showed signs of disease compared with 90% of the littermates. Therefore, IL-10 seemed to have a protective role in CIA, but seemed to exacerbate the arthritogenicity of anti-CII Abs. These data emphasize the importance of studying IL-10 in a defined genetic context in vivo, to understand its role in a complex disease like arthritis.

T lymphocytes are not required for the spontaneous development of entheseal ossification leading to marginal ankylosis in the DBA/1 mouse.

OBJECTIVE: Male mice of the DBA/1 inbred strain spontaneously develop polyarthritis and toe stiffness when they are > or =4 months old. The arthritis affects predominantly the proximal interphalangeal joints and the ankle of the hind limbs. The current study was aimed at determining the importance of T lymphocytes in this disease. METHODS: Histologic sections of hindpaws from arthritic DBA/1 mice were examined. The role of T lymphocytes was studied by using mice lacking either alpha/beta or gamma/delta T cells due to a deletion in T cell receptor beta (TCRbeta) or TCRdelta genes. RESULTS: Arthritis was associated with a massive proliferation of connective tissue (fibroblasts) in synovium and adjacent tissues. Chondroid and bone tissue outgrowth at the entheses generated periarticular osteophytes (enthesophytes) which were deposited on the unchanged margins of the preexisting bone. In some cases, the enthesophytes enlarged enough to bridge and fuse the bones by marginal ankylosis. Articular cartilage was essentially unaffected. Abnormal chondroid tissue formation was common in stiffened toes, suggesting that the same pathology may underlie both joint stiffness and arthritis. Dividing chondrocytes were commonly seen in tendons, but without correlation with arthritis or toe stiffness. Mice lacking alpha/beta or gamma/delta T cells developed arthritis at the same incidence as control littermates. CONCLUSION: The naturally occurring arthritis in male DBA/1 mice is a T cell-independent enthesopathy characterized by periarticular hyperostosis and marginal ankylosis. This suggests that the ossification leading to peripheral ankylosis of the joints in human enthesopathies, such as diffuse idiopathic skeletal hyperostosis and seronegative spondylarthropathies, is a T cell-independent process.

A new animal model for relapsing polychondritis, induced by cartilage matrix protein (matrilin-1).

Relapsing polychondritis (RP) differs from rheumatoid arthritis (RA) in that primarily cartilage outside diarthrodial joints is affected. The disease usually involves trachea, nose, and outer ears. To investigate whether the tissue distribution of RP may be explained by a specific immune response, we immunized rats with cartilage matrix protein (matrilin-1), a protein predominantly expressed in tracheal cartilage. After 2-3 weeks, some rats developed a severe inspiratory stridor. They had swollen noses and/or epistaxis, but showed neither joint nor outer ear affection. The inflammatory lesions involved chronic active erosions of cartilage. Female rats were more susceptible than males. The disease susceptibility was controlled by both MHC genes (f, l, d, and a haplotypes are high responders, and u, n, and c are resistant) and non-MHC genes (the LEW strain is susceptible; the DA strain is resistant). However, all strains mounted a pronounced IgG response to cartilage matrix protein. The initiation and effector phase of the laryngotracheal involvement causing the clinical symptoms were shown to depend on alphabeta T cells. Taken together, these results represent a novel model for RP: matrilin-1-induced RP. Our findings also suggest that different cartilage proteins are involved in pathogenic models of RP and RA.

Radiographic examinations as an aid to orthodontic diagnosis and treatment planning.

Seventy consecutive adolescents were examined to evaluate radiographic examinations as an aid to orthodontic diagnosis and treatment planning in combination with clinical examination. The clinical examination included dental impressions and extra- and intraoral photographs. The radiographic examination comprised a panoramic radiograph, a lateral cephalogram and six intraoral anterior periapical radiographs. Initially, only records from the clinical examination were used for diagnosis and treatment planning. If required, the dentist could choose any of the radiographs to accomplish the task. The number of radiographs ordered, the sequence of ordering and any change in diagnosis and treatment plan caused by the radiographs were registered. In 29% of the cases the initial diagnosis, based on the clinical examination, study models and photographs, coincided with the final diagnosis. In 93% of all cases the initial treatment plan coincided with the final one. Although the panoramic examination was the most common choice, it had only a minor effect on diagnostic and treatment decisions, while the cephalometric examination had a major impact on the diagnosis. In most cases the clinical examination, supplemented with study models and photographs, can provide adequate information for orthodontic treatment planning. The result stresses the importance of using individually based selection criteria for radiographic examination in order to prevent radiographs being obtained routinely.

Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats.

In rheumatoid arthritis peripheral cartilaginous joints are inflamed and eroded. One driving factor may be an immune response towards proteins in the cartilage. Here it is shown that cartilage oligomeric matrix protein (COMP), expressed specifically in cartilage, is arthritogenic in the rat. Both native and denatured rat COMP induced severe arthritis in selected rat strains. The arthritis occurred only in peripheral joints which were attacked by an erosive inflammatory process similar to that seen in the human disease. The disease was self-limited and no permanent destruction of joints was seen macroscopically. Disease development appeared to be dependent on an immune response to autologous (rat) COMP and not on cross-reactivity to other cartilage rat collagens (types II, IX and XI). The disease and the immune response to COMP were genetically controlled by the MHC; the RT1u and RT1l haplotypes were more susceptible than the a, c, d, f and n haplotypes. Both LEW and E3 gene backgrounds were highly permissive for disease induction. These findings suggest that the induction of arthritis with rat COMP represents a unique pathogenesis which is controlled by different genes compared with collagen-induced arthritis or adjuvant-induced arthritis.