pteryxin cost VPS and SNX transport many intracellular recep

VPS35 and SNX27 transport many intracellular receptors with broad functions. Those identified to date that regulate bone metabolism include the β1 and β2 adrenergic receptors, GPR177 — a receptor that regulates Wnt family member sorting () — and degradative RANKL transport in osteoclasts (). There are likely to be additional cargoes. Unsurprisingly, global VPS35 knockouts are early embryonic lethal, and global SNX27 knockouts exhibit a severe skeletal phenotype (). Specific VPS35 knockdown in the osteoblast lineage, using osteocalcin-targeted-Cre, resulted in mildly lowered bone mass in the primary spongiosa, assessed at a single time point (). The cellular mechanism responsible is unclear – serum pteryxin cost showed elevated markers of bone formation and elevated serum calcium, suggesting that both bone formation and resorption are high with an imbalance in favour of resorption; no histomorphometry is reported. Further work is needed to determine the basal effect of VPS35 deletion in osteoblasts. Due to retromer\'s multiple functions, the key question from a therapeutic perspective is how PTH anabolic action is modified in mice with specific VPS35 or SNX27 deletion in osteoblasts; this must be performed in vivo because it is not possible to model PTH anabolic action in vitro. Mice with VPS35 deletion targeted to osteoblasts showed a greater increase in bone mass in the primary spongiosa in response to PTH compared to controls (). It must be noted that the primary spongiosa is the region where new trabeculae are formed from mineralized cartilage at the growth plate, and bone mass in this region is controlled by many biological processes in addition to bone formation and resorption, such as chondrocyte differentiation and angiogenesis (). Increased bone mass in this region does not relate directly to bone remodelling in mature bone. For this reason it is not yet clear whether VPS35 depletion in osteoblasts shifts the balance of PTH treatment to favour an anabolic effect by reducing its pro-osteoclastic action. Although an impaired osteoclastic response to PTH treatment was observed when osteoclast precursors were co-cultured with osteoblasts deficient in VPS35 and analysis at a single time point showed low RANKL mRNA levels (), this is suggestive only. It remains to be clarified whether this reflects reduced RANKL production in response to PTH, or a shorter duration of RANKL response, or if the effect in vivo is osteoclast-mediated at all.
It is generally more difficult to publish negative than positive scientific data, although everyone acknowledges how useful negative findings can be. This issue of presents such negative results that are nevertheless valuable. Gibb et al. () have addressed the question of the intracellular machinery pertaining to inflammation and its potential role in regulating alloimmunization to red blood cell (RBC) antigens. Gibb et al. attempted to test the role of mobilizing the inflammasome of innate immune cells in an experimental (mouse) model of alloimmunization. They sought to model real-life conditions of transfusion by providing stored RBC components (RBCCs). RBCC storage was previously shown to increase alloimmunization in the mouse, a model which simplifies the alloantigenic barriers. The relevance of old vs fresh RBCCs in humans is not yet ascertained with respect to medical outcomes (), though there is common sense evidence that fresh cells may do better than old ones (). Studies investigating the effect of RBC storage time on alloimmunization in humans have given conflicting results, with a clear association observed in some settings, but no association in others. In the current report, the authors hypothesized that damage-associated molecular patterns (DAMPs) share responsibility in inducing inflammation and subsequent alloimmunization. Storage for a limited period of time is indeed necessary to generate a safe blood component (BC) inventory, although it also results in the storage lesion (). To investigate their hypothesis, Gibb et al. focused on a major inflammasome molecule i.e. NLRP3, which is a member of the NOD-like receptor family that activates caspase-1 and triggers the release of IL-1β and IL-18. Both of these pro-inflammatory cytokines fuel the inflammation linked-process of antigen presentation and the epitope specific T lymphocyte response to antigen presenting cells (APCs). The authors have used well-characterized inflammasome KO mice, and elegantly proceeded with conventional dendritic cell (DC) depletion studies. They confirm the profound effect of storage on alloimmunization in this clear-cut model but also observe that NLRP3/caspase-1 is not required for the effect ().