Publications

OBJECTIVE

Obesity is associated with high rates of disability in the general population. The nature of the relationship between obesity and disability in systemic lupus erythematosus (SLE), a condition with a high background rate of disability, is unknown.

METHODS

Data were from 2 interviews, 4 years apart, of a longitudinal cohort of individuals with SLE (n = 716 women). Body mass index (BMI) was calculated from self-reported height and weight; obesity was classified by usual (BMI ≥30) and revised (BMI ≥26.8) definitions. Three measures of functioning were examined: the Short Form 36 (SF-36) Health Survey physical function (PF) subscale, Valued Life Activities (VLA) Disability Questionnaire, and employment. Multivariate analyses controlled for demographics, SLE duration and disease activity, glucocorticoid use, depression, and comorbidities. Prospective analyses also controlled for baseline function.

RESULTS

At a BMI of ≥30, 27.8% of the subjects were obese; at a BMI of ≥26.8, 40.6% of the subjects were obese. Regardless of obesity definition, obese women exhibited poorer baseline function, with decrements ranging from 20-33% depending on the functional measure and obesity definition. With a BMI of ≥26.8, the adjusted SF-36 PF scores were 4.3 points lower for obese women (P < 0.0001), VLA difficulty was 0.09 higher (P = 0.01), and odds of employment were 80% of nonobese women (odds ratio 0.8, 95% confidence interval 0.5-1.1). At the 4-year followup, women who were obese at baseline had poorer function and experienced greater functional declines.

CONCLUSION

Obesity was associated with clinically significant negative effects on function, both concurrently and prospectively. This negative impact occurred at a lower BMI than is often considered problematic clinically. Because of the high rate of SLE-related disability, addressing preventable risk factors such as obesity may improve long-term SLE outcomes.

Activation of Raf/Ras/mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase signaling and elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) are associated with von Hippel-Lindau gene alterations in renal cell carcinoma. We postulated that the degree of MEK activation was related to graded expression of MT1-MMP and the resultant phenotype of renal epithelial tumors. Madin Darby canine kidney epithelial cells transfected with a MEK1 expression plasmid yielded populations with morphologic phenotypes ranging from epithelial, mixed epithelial/mesenchymal to mesenchymal. Clones were analyzed for MEK1 activity, MT1-MMP expression and extent of epithelial-mesenchymal transition. Phenotypes of the MDCK-MEK1 clones were evaluated in vivo with nu/nu mice. Tissue microarray of renal cell cancers was quantitatively assessed for expression of phosphorylated MEK1 and MT1-MMP proteins and correlations drawn to Fuhrman nuclear grade. Graded increases in the MEK signaling module were associated with graded induction of epithelial-mesenchymal transition of the MDCK cells and induction of MT1-MMP transcription and synthesis. Inhibition of MEK1 and MT1-MMP activity reversed the epithelial-mesenchymal transition. Tumors generated by epithelial, mixed epithelial/mesenchymal and mesenchymal MDCK clones demonstrated a gradient of phenotypes extending from well-differentiated, fully encapsulated non-invasive tumors to tumors with an anaplastic morphology, high Fuhrman nuclear score, neoangiogenesis and invasion. Tumor microarray demonstrated a statistically significant association between the extent of phosphorylated MEK1, MT1-MMP expression and nuclear grade. We conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade. Phosphorylated MEK1 and MT1-MMP may represent novel, and mechanistic, biomarkers for the assessment of renal cell carcinoma.