Objective. To examine the pathogenetic mechanisms of osteoarthritis (OA)-like changes in Col9a1 ؊/؊ mice, which are deficient in type IX collagen.Methods. Knee joints and temporomandibular joints (TMJs) from Col9a1 ؊/؊ mice and their wild-type (Col9a1 ؉/؉ ) littermates were examined by light microscopy. Immunohistochemical staining was performed to examine the expression of matrix metalloproteinase 3 (MMP-3) and MMP-13, degraded type II collagen, and the discoidin domain receptor 2 (DDR-2) in knee joints. Cartilage mechanics were also evaluated for compressive properties by microindentation testing of the tibial plateau and for tensile properties by osmotic loading of the femoral condyle.Results. Histologic analysis showed agedependent OA-like changes in the knee and TMJs of Col9a1 ؊/؊ mice starting at the age of 3 months. At the age of 6 months, enhanced proteoglycan degradation was observed in the articular cartilage of the knee and TMJs of the mutant mice. The expression of MMP-13 and DDR-2 protein and the amount of degraded type II collagen were higher in the knee joints of Col9a1 ؊/؊ mice than in their wild-type littermates at the age of 6 months. Changes in cartilage mechanics were observed in the femoral and tibial plateaus of Col9a1 ؊/؊ mice at 6 months, including a decrease in the compressive modulus and uniaxial modulus. At 3 and 6 months of age, tibial cartilage in Col9a1 ؊/؊ mice was found to be more permeable to fluid flow, with an associated compromise in the fluid pressurization mechanism of load support. All of these changes occurred only at medial sites.Conclusion. Lack of type IX collagen in Col9a1 ؊/؊ mice results in age-dependent OA-like changes in the knee joints and TMJs.

Primary leptomeningeal melanoma (PLM) is a rare type of cancer that represents a major clinical and molecular diagnostic challenge. A definitive diagnosis requires consistent magnetic resonance imaging findings and cerebrospinal fluid (CSF) cytology. Due to the small number of malignant cells in the CSF, routine testing for mutations in the gene is difficult, which prevents the stratification of these patients to potentially beneficial therapies. We herein present the case of a 62-year old man with CSF cytology indicating PLM, where mutation testing, from cell-free (cf) tumor DNA isolated from the CSF and plasma was implemented to guide clinical decision making. Testing for mutation from the CSF and plasma was technically feasible, yielded concordant results, and guided the treatment for this patient. This case suggests that mutation testing of cfDNA isolated from the CSF is technically feasible and may guide therapy in cases where a tissue diagnosis is not possible for PLM and other malignancies with defined oncogenic driver mutations.

Collagen type II (CII) induced arthritis (CIA) in mice is an experimental model for rheumatoid arthritis. Induction with non-self (e.g. human) CII induces severe arthritis whereas the mice are less susceptible to induction with self CII (i.e. mouse). To analyse whether an autoimmune response to human CII can develop and is pathogenic the authors have established transgenic mice expressing human CII in cartilage and backcrossed them into two different gene backgrounds susceptible to CIA (DBA/1 and C3H.Q). The transgenic human CII expression was restricted to cartilage and did not disturb cartilage morphology or lead to chondrodystrophy. In addition, development of stress-induced arthritis was not affected by the transgene. The cartilage specific expression of human CII reduced, but did not eliminate, the susceptibility to CIA irrespective of the species source (human, bovine, chick, rat) of CII used for immunization. A common denominator between these heterologous CII in comparison with mouse CII is the previously defined CII 256-270 epitope. An expression level dependent T-cell tolerance was seen in this epitope as well as to the entire CII. However, all human transgenic mouse lines could still mount significant autoreactive T-and B-cell responses. Approximately 10% of the transgenic mice developed arthritis after immunization with human CII. These findings show, therefore, that cartilage-located human CII induce tolerance but can nevertheless be a target for development of arthritis.

No abstract