Objective. To investigate whether heterozygosity for a loss-of-function mutation in the gene encoding the ␣1 chain of type XI collagen (Col11a1) in mice (chondrodysplasia, cho) causes osteoarthritis (OA), and to understand the biochemical and biomechanical effects of this mutation on articular cartilage in knee and temporomandibular (TM) joints.Methods. Articular cartilage from the knee and TM joints of mice heterozygous for cho (cho/؉) and their wild-type littermates (؉/؉) was examined. The morphologic properties of cartilage were evaluated, and collagen fibrils were examined by transmission electron microscopy. Immunohistochemical staining was performed to examine the protein expression levels of matrix metalloproteinase 3 (MMP-3) and MMP-13 in knee joints. In 6-month-old animals, fixed-charge density was determined using a semiquantitative histochemical method, and tensile stiffness was determined using an osmotic loading technique.Results. The diameter of collagen fibrils in articular cartilage of knee joints from heterozygous cho/؉ mice was increased relative to that in control cartilage, and histologic analysis showed OA-like degenerative changes in knee and TM joints, starting at age 3 months. The changes became more severe with aging. At 3 months, protein expression for MMP-3 was increased in knee joints from cho/؉ mice. At 6 months, protein expression for MMP-13 was higher in knee joints from cho/؉ mice than in joints from their wild-type littermates, and negative fixed-charge density was significantly decreased. Moreover, tensile stiffness in articular cartilage of knee joints from cho/؉ mice was moderately reduced and was inversely correlated with the increase in articular cartilage degeneration. Conclusion. Heterozygosity for a loss-of-function mutation inCol11a1 results in the development of OA in the knee and TM joints of cho/؉ mice. Morphologic and biochemical evidence of OA appears to precede significant mechanical changes, suggesting that the cho mutation leads to OA through a mechanism that does not initially involve mechanical factors.Osteoarthritis (OA) is the most frequently occurring degenerative joint disease in the US (1). Although the precise mechanisms by which OA is initiated and progresses are largely unknown, there is growing evidence suggesting that single-gene mutations can, in some cases, be predisposing factors for the disease. For instance, mutations in the genes coding for type II collagen (COL2A1), type IX collagen (COL9A1, COL9A2, and COL9A3), and type XI collagen (COL11A1 and COL11A2) are responsible for earlyonset OA associated with variable degrees of chondrodysplasia in humans (2-6). Understanding the mechanisms underlying the OA caused by collagen mutations will not only broaden our knowledge of OA pathogenesis but may also provide valuable information for the identification of novel therapeutic targets for the treatment of OA.We have previously identified a mutation in Col11a1 as the genetic cause of chondrodysplasia (cho) in mice. The mutation, a single-nucleotide dele...

Summary Objective The objective of this study is to characterize mouse temporomandibular joint (TMJ) following partial discectomy, since there is no documentation of whether or not partial discectomy can induce early-onset osteoarthritis (OA) in mouse TMJ. Methods Partial discs of TMJ in mice were removed by microsurgery. Histology was performed to characterize articular cartilages from the TMJ of mice. The morphology of the articular cartilages was evaluated using a modified Mankin scoring system. Immunohistostaining was carried out to examine the expression of discoidin domain receptor 2 (Ddr2), a type II collagen receptor, matrix metalloproteinase 13 (Mmp-13), and Mmp-derived type II collagen fragments in the articular cartilage of condyles from the mouse TMJ. Results Articular cartilage degeneration was seen in the mouse TMJ post discectomy, including increased proteoglycan staining in the extracellular matrix at 4 weeks, the appearance of chondrocyte clusters at 8 weeks, reduced proteoglycan staining and fibrillation at 12 weeks and the loss of articular cartilage at 16 weeks. Increased immunostaining for Ddr2, Mmp-13, and Mmp-derived type II collagen fragments was detected. Conclusion Results indicate that partial discectomy induces early-onset OA in mouse TMJ and that increased expression of Mmp-13, likely due to the elevated expression of Ddr2, may be one of the factors responsible for the early-onset OA in mouse TMJ.

Summary Background Psoriasis is a common, chronic and inflammatory disease of the skin, which has been associated with depression in cross-sectional studies with limited adjustment for confounders. Objectives In this prospective cohort study, we investigated the risk of incident depression among individuals with psoriasis and psoriatic arthritis (PsA). Methods We included 50 750 US female nurses from the Nurses’ Health Study who were free of depression at baseline in 2000. Those participants who had ever self-reported clinician-diagnosed depression or regular use of antidepressants, or had a Mental Health Inventory score of ≤ 52 were excluded. In 2008, we retrospectively asked participants if they had ever received a physician’s diagnosis of psoriasis or PsA. We defined depression as self-report of clinician-diagnosed depression or regular use of antidepressant medication. Time-dependent Cox proportional hazard models were used to estimate age and multivariate-adjusted relative risks (RRs) of clinical depression. Results After adjusting for covariates including body mass index, physical activity, smoking and the presence of major chronic conditions, the multivariate-adjusted RRs of clinical depression were 1.29 [95% confidence interval (CI) 1.10–1.52] for women with psoriasis and 1.52 (95% CI 1.06–2.19) for women with psoriasis and concomitant PsA, compared with women without psoriasis. Conclusions We found an increased risk of depression in US women with psoriasis compared with those without psoriasis. This risk was higher in those who reported concomitant PsA. Future studies are needed to confirm these findings in other populations and to identify pathophysiological mechanisms linking psoriasis to depression.

Women with MS had a significantly higher prevalence of RLS and daytime sleepiness and an increased risk of developing RLS in the future.

In human genetic studies of schizophrenia, we uncovered copy-number variants in RAPGEF6 and RAPGEF2 genes. To discern the effects of RAPGEF6 deletion in humans, we investigated the behavior and neural functions of a mouse lacking Rapgef6. Rapgef6 deletion resulted in impaired amygdala function measured as reduced fear conditioning and anxiolysis. Hippocampal-dependent spatial memory and prefrontal cortex-dependent working memory tasks were intact. Neural activation measured by cFOS phosphorylation demonstrated a reduction in hippocampal and amygdala activation after fear conditioning, while neural morphology assessment uncovered reduced spine density and primary dendrite number in pyramidal neurons of the CA3 hippocampal region of knockout mice. Electrophysiological analysis showed enhanced long-term potentiation at cortico–amygdala synapses. Rapgef6 deletion mice were most impaired in hippocampal and amygdalar function, brain regions implicated in schizophrenia pathophysiology. The results provide a deeper understanding of the role of the amygdala in schizophrenia and suggest that RAPGEF6 may be a novel therapeutic target in schizophrenia.