The immunoglobulin superfamily represents a diverse set of cell-cell contact proteins and includes well-studied members such as NCAM1, DSCAM, L1 or the contactins which are strongly expressed in the nervous system. In this review we put our focus on the biological function of a less understood subgroup of Ig-like proteins composed of CAR (coxsackievirus and adenovirus receptor), CLMP (CAR-like membrane protein) and BT-IgSF (brain and testis specific immunoglobulin superfamily). The CAR-related proteins are type I transmembrane proteins containing an N-terminal variable (V-type) and a membrane proximal constant (C2-type) Ig domain in their extracellular region which are implicated in homotypic adhesion. They are highly expressed during embryonic development in a variety of tissues including the nervous system whereby in adult stages the protein level of CAR and CLMP decreases, only BT-IgSF expression increases within age. CAR-related proteins are concentrated at specialized cell-cell communication sites such as gap or tight junctions and are present at the plasma membrane in larger protein complexes. Considerable progress has been made on the molecular structure and interactions of CAR while research on CLMP and BT-IgSF is at an early stage. Studies on mouse mutants revealed biological functions of CAR in the heart and for CLMP in the gastrointestinal and urogenital systems. Furthermore, CAR and BT-IgSF appear to regulate synaptic function in the hippocampus.
Bone healing has been described to be most efficient if the early inflammatory phase is resolved timely. When the inflammation elevates or is permanently established, bone healing becomes impaired and, moreover, bone destruction often takes place. Systemic disorders such as diabetes and bone diseases like arthritis and osteoporosis are associated with sustained inflammation and delayed bone healing. One goal of biomaterial research is the development of materials/surface modifications which support the healing process by inhibiting the inflammatory bone erosion and suppressing pro-inflammatory mediators and by that promoting the bone repair process. In the present study, the influence of artificial extracellular matrices (aECM) on the interleukin (IL)-1β-induced pro-inflammatory response of human mesenchymal stromal cells (hMSC) was studied. hMSC cultured on aECM composed of collagen I and high-sulfated glycosaminoglycan (GAG) derivatives did not secrete IL-6, IL-8, monocyte chemoattractant protein-1, and prostaglandin E2 in response to IL-1β. The activation and nuclear translocation of nuclear factor κBp65 induced by IL-1β, tumor necrosis factor-α or lipopolysaccharide was abrogated. Furthermore, these aECM promoted the osteogenic differentiation of hMSC as determined by an increased activity of tissue non-specific alkaline phosphatase (TNAP); however, the aECM had no effect on the IL-1β-induced TNAP activity. These data suggest that aECM with high-sulfated GAG derivatives suppress the formation of pro-inflammatory mediators and simultaneously promote the osteogenic differentiation of hMSC. Therefore, these aECM might offer an interesting approach as material/surface modification supporting the bone healing process.
26Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of 27 caveolae, but its physiological function has remained unclear. Here, we found that global genetic ablation 28 of EHD2 in mice led to increased fat accumulation. This organismic phenotype was paralleled at the 29 cellular level by increased lipid uptake via a caveolae-, dynamin-and CD36-dependent pathway, an 30 elevated number of detached caveolae and higher caveolar mobility. Furthermore, EHD2 expression itself 31 was down-regulated in the visceral fat of two obese mouse models and obese patients. Our data suggest 32 that EHD2 controls a cell-autonomous, caveolae-dependent lipid uptake pathway and suggest that low 33 EHD2 expression levels are linked to obesity. 34 35 36 Keywords: EHD2, caveolae, fatty acid uptake, lipid metabolism, obesity 37 38 occurrence of compensatory mechanisms. First, we looked for changes of adiponectin, leptin and insulin 126 plasma levels but did not detect any significant difference in mice lacking EHD2 compared to EHD2 del/+ 127 mice (Fig. S3). Free fatty acid concentration in blood plasma was slightly reduced in EHD2 del/del 128 suggesting a possible increase in fatty acid uptake (Fig. S3). Furthermore, we observed a down-regulation 129 of genes involved in de novo lipogenesis in isolated WAT obtained EHD2 del/del vs. EHD2 del/+ mice or in 130 primary adipocyte cell cultures ( Fig. S5B-D) suggesting that downregulation of lipogenesis is an active 131 mechanism that partially compensates for the increased lipid accumulation. 132 133 134
The coxsackievirus and adenovirus receptor (CAR, CXADR) is a multi-functional cell adhesion molecule which forms with CLMP, BT-IgSF, ESAM and CTX a structural subgroup within the Ig superfamily. These proteins share an overall domain organization with two extracellular Ig domains, a transmembrane region and a cytoplasmic tail which includes a PDZ binding motif. CAR is strongly expressed in brain and heart during embryonic development and becomes down-regulated in early postnatal stages. Cell adhesion experiments, binding studies and as well as crystallographic investigations on the extracellular domain reveal a flexible ectodomain for CAR that mediates homophilic and heterophilic binding. Several animal models showed an essential role for CAR during embryonic heart development and for electrical conduction between neighboring cardiomyocytes at mature stages. CAR gets re-expressed in diseased or damaged cardiac tissue, probably to induce regeneration and remodeling of the cardiac muscle.
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