The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's syndrome.

Sjogren's syndrome (SS) is a complex autoimmune disease that primarily affects salivary and lacrimal glands and is associated with high morbidity. Although the prevailing dogma is that immune system pathology drives SS, increasing evidence points to structural defects, including defective E-cadherin adhesion, to be involved in its etiology. We have shown that E-cadherin has pivotal roles in the development of the mouse salivary submandibular gland (SMG) by organizing apical-basal polarity in acinar and ductal progenitors and by signaling survival for differentiating duct cells. Recently, E-cadherin junctions have been shown to interact with effectors of the Hippo signaling pathway, a core pathway regulating the organ size, cell proliferation, and differentiation. We now show that Hippo signaling is required for SMG-branching morphogenesis and is involved in the pathophysiology of SS. During SMG development, a Hippo pathway effector, TAZ, becomes increasingly phosphorylated and associated with E-cadherin and α-catenin, consistent with the activation of Hippo signaling. Inhibition of Lats2, an upstream kinase that promotes TAZ phosphorylation, results in dysmorphogenesis of the SMG and impaired duct formation. SMGs from non-obese diabetic mice, a mouse model for SS, phenocopy the Lats2-inhibited SMGs and exhibit a reduction in E-cadherin junctional components, including TAZ. Importantly, labial specimens from human SS patients display mislocalization of TAZ from junctional regions to the nucleus, coincident with accumulation of extracellular matrix components, fibronectin and connective tissue growth factor, known downstream targets of TAZ. Our studies show that Hippo signaling has a crucial role in SMG-branching morphogenesis and provide evidence that defects in this pathway are associated with SS in humans.

The influence of laser-textured dentinal surface on bond strength.

OBJECTIVE: To assess the influence of laser-textured surfaces on the adhesion of composite to dentin after being rotary prepared. METHODS: Thirty healthy teeth were kept in 0.1% thymol solution prior to being ground down to dentin to create a 4 × 4 mm² flat surface. Teeth were divided into 3 groups (n=10). Groups 1 and 2 utilized the prototype Erbium doped, Yttrium-Aluminum-Garnet Er:YAG laser by Dental Photonics, Inc. A single pulse was delivered to each spot to create an equally spaced square 4 × 4 mm² matrix of micro craters. All craters had 100 µm diameter/45 µm depth; two different spacing patterns were prepared in Groups 1 and 2. In Group 1, distance between crater centers was 50 µm; Group 2 had 100 µm. In Group 3 (control), 10 samples were prepared without laser texturing. G-bond (GC America) was applied to testing area of all samples in all groups according to manufacturer's instructions. Bonding resin was applied and shear-bond strength tests were employed using an Instron machine to measure adhesive strength. RESULTS: One-way analysis of variance (ANOVA) was used to compare the 3 groups. Pair wise t-tests implementing the Bonferroni correction for multiple comparisons found a statistically significant difference between Group 3 and Group 2 (p=0.019) but no statistically significant difference between Group 3 and Group 1 (p=0.263) or Group 1 and Group 2 (p=0.743). SIGNIFICANCE: The bond strengths between bonded composite to laser-textured dentinal surfaces with larger spacing patterns are greater than that of non-textured surfaces.

Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits glucose-induced signalling in proximal tubular cells.

BACKGROUND: In the diabetic kidney, stimulation of mitogen-activated protein kinases (MAPKs) leads to extracellular matrix protein synthesis. In the proximal tubule, angiotensin-(1-7) [Ang-(1-7)] blocks activation of MAPKs by angiotensin II. We studied the effect of Ang-(1-7) on signalling responses in LLC-PK(1) cells in normal (5 mM) or high (25 mM) glucose. METHODS: The p38 MAPK was assayed by immunoblot, Src homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity was measured after immunoprecipitation, cell protein synthesis was determined by [(3)H]-leucine incorporation and transforming growth factor-beta1 (TGF-beta1), fibronectin and collagen IV were assayed by immunoblots and/or ELISA. RESULTS: High glucose stimulated p38 MAPK. This response was inhibited by Ang-(1-7) in a concentration-dependent fashion, an effect reversed by the receptor Mas antagonist A-779. Ang-(1-7) increased SHP-1 activity, via the receptor Mas. An inhibitor of tyrosine phosphatase, phenylarsine oxide, reversed the inhibitory effect of Ang-(1-7) on high glucose-stimulated p38 MAPK. Ang-(1-7) inhibited high glucose-stimulated protein synthesis, and blocked the stimulatory effect of glucose on TGF-beta1. Conversely, Ang-(1-7) had no effect on glucose-stimulated synthesis of fibronectin or collagen IV. CONCLUSIONS: These data indicate that in proximal tubular cells, binding of Ang-(1-7) to the receptor Mas stimulates SHP-1, associated with the inhibition of glucose-stimulated p38 MAPK. Ang-(1-7) selectively inhibits glucose-stimulated protein synthesis and TGF-beta1. In diabetic nephropathy, Ang-(1-7) may partly counteract the profibrotic effects of high glucose.