Tctex-1, a Novel Interaction Partner of Rab3D, Is Required for Osteoclastic Bone Resorption ▿

Vesicular transport along microtubules must be strictly regulated to sustain the unique structural and functional polarization of bone-resorbing osteoclasts. However, the molecular mechanisms bridging these vesicle-microtubule interactions remain largely obscure. Rab3D, a member of the Rab3 subfamily (Rab3A/B/C/D) of small exocytotic GTPases, represents a core component of the osteoclastic vesicle transport machinery. Here, we identify a new Rab3D-interacting partner, Tctex-1, a light chain of the cytoplasmic dynein microtubule motor complex, by a yeast two-hybrid screen. We demonstrate that Tctex-1 binds specifically to Rab3D in a GTP-dependent manner and co-occupies Rab3D-bearing vesicles in bone-resorbing osteoclasts. Furthermore, we provide evidence that Tctex-1 and Rab3D intimately associate with the dynein motor complex and microtubules in osteoclasts. Finally, targeted disruption of Tctex-1 by RNA interference significantly impairs bone resorption capacity and mislocalizes Rab3D vesicles in osteoclasts, attesting to the notion that components of the Rab3D-trafficking pathway contribute to the maintenance of osteoclastic resorptive function

Cellular and molecular events in acute pancreatitis

Acute pancreatitis (AP) is a common disease in which the underlying mechanisms of the local initiating events in the pancreas, the systemic dissemination of the inflammatory response and the development of remote organ dysfunction have not been fully clarified. AP is still associated with substantial morbidity and mortality. Clinical therapeutic strategies for AP have so far been mainly directed at supportive critical care. After the initial injury to the pancreatic acinar cells, the inflammatory mediators released from the inflamed acini trigger activating cascades through immunocompetent cells, leading to the development of systemic inflammatory response syndrome and multiple organ dysfunction syndrome. These damaged, inflamed acinar cells interact with activated, immigrated immune cells and inflammatory mediators and therefore amplify the inflammatory response in AP. Of these immune cells, neutrophils, monocytes/macrophages and T lymphocytes play critical roles in the pathogenesis of AP. Substantial evidence exists demonstrating the importance of inflammatory mediators such as cytokines, chemokines and adhesion molecules in the initiation of the progression of AP. Inflammatory mediators in damaged, inflamed acinar cells and activated immunocompetent cells are closely regulated through cellular signalling pathways, e.g. those involving nuclear factor-κB, mitogen-activated protein kinase, reactive oxygen species and protein kinase C. Therefore, cellular and molecular events are crucial to the pathophysiological mechanisms underlying AP. Single- or multi-modal treatment regimens directed at regulating different steps in the signalling pathways could represent future modes of management