👤 Begoña Martínez de Tejada

Osteoarthritis (OA), the most common arthritic condition in humans, is characterized by the progressive degeneration of articular cartilage accompanied by chronic joint pain. Inflammatory mediators, such as cytokines and prostaglandin E(2) (PGE(2)) that are elevated in OA joints, play important roles in the progression of cartilage degradation and pain-associated nociceptor sensitivity. We have found that the nuclear receptor family transcription factors Liver X Receptors (LXRalpha and -beta) are expressed in cartilage, with LXRbeta being the predominant isoform. Here we show that genetic disruption of Lxrbeta gene expression in mice results in significantly increased proteoglycan (aggrecan) degradation and PGE(2) production in articular cartilage treated with IL-1beta, indicating a protective role of LXRbeta in cartilage. Using human cartilage explants, we found that activation of LXRs by the synthetic ligand GW3965 significantly reduced cytokine-induced degradation and loss of aggrecan from the tissue. Furthermore, LXR activation dramatically inhibited cytokine-induced PGE(2) production by human osteoarthritic cartilage as well as by a synovial sarcoma cell line. These effects were achieved at least partly by repression of the expression of ADAMTS4, a physiological cartilage aggrecanase, and of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, key enzymes in the PGE(2) synthesis pathway. Consistent with our in vitro observations, oral administration of GW3965 potently alleviated joint pain in a rat meniscal tear model of osteoarthritis. Show less

The need for a non-invasive diagnosis of the effects of ethanol in utero on the development of the intestine in humans led us to look for a serum marker of the structural integrity of the intestine. We propose apolipoprotein A-IV (apoA-IV) as a possible candidate. In humans this protein is synthesized only by intestinal mucosa, it is expressed in the enterocyte of the foetus from 20 weeks of gestation, and it is released to the blood stream after synthesis. We measured the levels of apoA-IV in the umbilical cord serum of neonates whose mothers had consumed alcohol during pregnancy and neonates born to women who had not (controls). The gestational age at delivery of the cases studied ranged from 36 to 42 weeks. ELISA and Western blot analysis were used. There was no difference in the mean body weight of neonates from either group. Nevertheless, exposure to ethanol in utero significantly reduced (by about 30%) the apoA-IV levels in serum at birth, regardless of body weight. Our findings suggest that circulating apoA-IV levels could be used as a clinical marker of the prenatal effects of ethanol on the structural integrity of the intestine. Neonatal diagnosis of these intestinal effects could improve post-natal outcome. Show less