The coordinated activities of collagen VI and XII in maintenance of tissue structure, function and repair: evidence for a physical interaction.

Collagen VI and collagen XII are structurally complex collagens of the extracellular matrix (ECM). Like all collagens, type VI and XII both possess triple-helical components that facilitate participation in the ECM network, but collagen VI and XII are distinct from the more abundant fibrillar collagens in that they also possess arrays of structurally globular modules with the capacity to propagate signaling to attached cells. Cell attachment to collagen VI and XII is known to regulate protective, proliferative or developmental processes through a variety of mechanisms, but a growing body of genetic and biochemical evidence suggests that at least some of these phenomena may be potentiated through mechanisms that require coordinated interaction between the two collagens. For example, genetic studies in humans have identified forms of myopathic Ehlers-Danlos syndrome with overlapping phenotypes that result from mutations in either collagen VI or XII, and biochemical and cell-based studies have identified accessory molecules that could form bridging interactions between the two collagens. However, the demonstration of a direct or ternary structural interaction between collagen VI or XII has not yet been reported. This Hypothesis and Theory review article examines the evidence that supports the existence of a functional complex between type VI and XII collagen in the ECM and discusses potential biological implications.

Two-step regulation by matrix Gla protein in brown adipose cell differentiation.

OBJECTIVE: Bone morphogenetic protein (BMP) signaling is intricately involved in adipose tissue development. BMP7 together with BMP4 have been implicated in brown adipocyte differentiation but their roles during development remains poorly specified. Matrix Gla protein (MGP) inhibits BMP4 and BMP7 and is expressed in endothelial and progenitor cells. The objective was to determine the role of MGP in brown adipose tissue (BAT) development. METHODS: The approach included global and cell-specific Mgp gene deletion in combination with RNA analysis, immunostaining, thermogenic activity, and in vitro studies. RESULTS: The results revealed that MGP directs brown adipogenesis at two essential steps. Endothelial-derived MGP limits triggering of white adipogenic differentiation in the perivascular region, whereas MGP derived from adipose cells supports the transition of CD142-expressing progenitor cells to brown adipogenic maturity. Both steps were important to optimize the thermogenic function of BAT. Furthermore, MGP derived from both sources impacted vascular growth. Reduction of MGP in either endothelial or adipose cells expanded the endothelial cell population, suggesting that MGP is a factor in overall plasticity of adipose tissue. CONCLUSION: MGP displays a dual and cell-specific function in BAT, essentially creating a "cellular shuttle" that coordinates brown adipogenic differentiation with vascular growth during development.

Association of serum magnesium and distal symmetric peripheral neuropathy among Filipino patients with Type 2 Diabetes Mellitus

Objective@#This study aims to determine the association of serum magnesium with distal symmetric peripheral neuropathy among persons with type 2 diabetes mellitus (DM).@*Methodology@#A cross-sectional analytical study among adult Filipinos with Type 2 DM. Logistic regression was used to determine the association of serum magnesium with DSPN diagnosed by the Michigan Neuropathy Screening Instrument. The null hypothesis was rejected at 0.05α-level of significance.@*Results@#The average serum magnesium levels were similar between those with versus without DSPN (2.06 ± 0.32 vs 2.05 ± 0.23, p = 0.873); the same was seen for corrected magnesium. There is insufficient evidence to demonstrate a significant statistical difference between those with and without DSPN in relation to glycemic control (HbA1c and FBS). Likewise, there is no significant statistical correlation between serum magnesium levels with HbA1c, FBS, BMI, or duration of diabetes.@*Conclusion@#This present study could not demonstrate any association between DSPN and serum magnesium, even after adjusting for age, sex, and comorbidity.

Cell Transitions Contribute to Glucocorticoid-Induced Bone Loss.

Glucocorticoid-induced bone loss is a toxic effect of long-term therapy with glucocorticoids resulting in a significant increase in the risk of fracture. Here, we find that glucocorticoids reciprocally convert osteoblast-lineage cells into endothelial-like cells. This is confirmed by lineage tracing showing the induction of endothelial markers in osteoblast-lineage cells following glucocorticoid treatment. Functional studies show that osteoblast-lineage cells isolated from glucocorticoid-treated mice lose their capacity for bone formation but simultaneously improve vascular repair. We find that the glucocorticoid receptor directly targets Foxc2 and Osterix, and the modulations of Foxc2 and Osterix drive the transition of osteoblast-lineage cells to endothelial-like cells. Together, the results suggest that glucocorticoids suppress osteogenic capacity and cause bone loss at least in part through previously unrecognized osteoblast-endothelial transitions.

GSK3ß Inhibition Ameliorates Atherosclerotic Calcification.

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to atherosclerotic calcification. In a previous study, we showed that glycogen synthase kinase-3ß (GSK3ß) inhibition induced ß-catenin and reduced mothers against DPP homolog 1 (SMAD1) in order to redirect osteoblast-like cells towards endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency and diabetic Ins2Akita/wt mice. Here, we report that GSK3ß inhibition or endothelial-specific deletion of GSK3ß reduces atherosclerotic calcification. We also find that alterations in ß-catenin and SMAD1 induced by GSK3ß inhibition in the aortas of Apoe-/- mice are similar to Mgp-/- mice. Together, our results suggest that GSK3ß inhibition reduces vascular calcification in atherosclerotic lesions through a similar mechanism to that in Mgp-/- mice.

GSK3ß Inhibition Reduced Vascular Calcification in Ins2Akita/+ Mice.

Endothelial-mesenchymal transition (EndMT) drives the endothelium to contribute to vascular calcification in diabetes mellitus. In our previous study, we showed that glycogen synthase kinase-3ß (GSK3ß) inhibition induces ß-catenin and reduces mothers against DPP homolog 1 (SMAD1) to direct osteoblast-like cells toward endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency. Here, we report that GSK3ß inhibition reduces vascular calcification in diabetic Ins2Akita/wt mice. Cell lineage tracing reveals that GSK3ß inhibition redirects endothelial cell (EC)-derived osteoblast-like cells back to endothelial lineage in the diabetic endothelium of Ins2Akita/wt mice. We also find that the alterations in ß-catenin and SMAD1 by GSK3ß inhibition in the aortic endothelium of diabetic Ins2Akita/wt mice are similar to Mgp-/- mice. Together, our results suggest that GSK3ß inhibition reduces vascular calcification in diabetic arteries through a similar mechanism to that in Mgp-/- mice.

Regulating the cell shift of endothelial cell-like myofibroblasts in pulmonary fibrosis.

Pulmonary fibrosis is a common and severe fibrotic lung disease with high morbidity and mortality. Recent studies have reported a large number of unwanted myofibroblasts appearing in pulmonary fibrosis, and shown that the sustained activation of myofibroblasts is essential for unremitting interstitial fibrogenesis. However, the origin of these myofibroblasts remains poorly understood. Here, we create new mouse models of pulmonary fibrosis and identify a previously unknown population of endothelial cell (EC)-like myofibroblasts in normal lung tissue. We show that these EC-like myofibroblasts significantly contribute myofibroblasts to pulmonary fibrosis, which is confirmed by single-cell RNA sequencing of human pulmonary fibrosis. Using the transcriptional profiles, we identified a small molecule that redirects the differentiation of EC-like myofibroblasts and reduces pulmonary fibrosis in our mouse models. Our study reveals the mechanistic underpinnings of the differentiation of EC-like myofibroblasts in pulmonary fibrosis and may provide new strategies for therapeutic interventions.

Shifting osteogenesis in vascular calcification.

Transitions between cell fates commonly occur in development and disease. However, reversing an unwanted cell transition in order to treat disease remains an unexplored area. Here, we report a successful process of guiding ill-fated transitions toward normalization in vascular calcification. Vascular calcification is a severe complication that increases the all-cause mortality of cardiovascular disease but lacks medical therapy. The vascular endothelium is a contributor of osteoprogenitor cells to vascular calcification through endothelial-mesenchymal transitions, in which endothelial cells (ECs) gain plasticity and the ability to differentiate into osteoblast-like cells. We created a high-throughput screening and identified SB216763, an inhibitor of glycogen synthase kinase 3 (GSK3), as an inducer of osteoblastic-endothelial transition. We demonstrated that SB216763 limited osteogenic differentiation in ECs at an early stage of vascular calcification. Lineage tracing showed that SB216763 redirected osteoblast-like cells to the endothelial lineage and reduced late-stage calcification. We also found that deletion of GSK3ß in osteoblasts recapitulated osteoblastic-endothelial transition and reduced vascular calcification. Overall, inhibition of GSK3ß promoted the transition of cells with osteoblastic characteristics to endothelial differentiation, thereby ameliorating vascular calcification.

Impact of diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use, and statin use on presentation and outcomes in patients with giant cell arteritis.

AIM: Few, separate, small retrospective studies in giant cell arteritis (GCA) reported that patients: (a) with diabetes mellitus had less positive temporal artery biopsies (TAB); (b) on angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) experienced fewer relapses; and (c) on statins experienced the same frequency of clinical complications and relapses as non-exposed patients. This retrospective chart review study simultaneously investigated the impact of these 3 factors on a cohort of patients followed in 2 large Canadian centers (Hamilton and Toronto, ON). METHODS: One hundred and thirty-seven patients diagnosed with GCA between 1993 and 2015 were included in the study. Presenting symptoms, TAB results, disease complications and outcomes (relapses, duration of glucocorticoid use) were compared between exposed (diabetes/ACE/ARB/statin) and non-exposed patients, with adjustment for main potential confounding variables. RESULTS: Temporal artery biopsies was less often positive in patients with pre-existing diabetes (relative risk 0.24; 95% CI: 0.069-0.81). Patients who developed diabetes after diagnosis had a lower relapse-free survival (adjusted hazards ratio [HR] 0.28; 95% CI: 0.095-0.84). Patients taking ARBs prior to diagnosis were more likely to successfully discontinue glucocorticoids without a flare in the following 3 months (adjusted HR 2.46; 95% CI: 1.2-5.3). Clinical complications and relapse rates did not differ between patients on statin therapy or not. CONCLUSION: Diabetic patients with GCA were less likely to have a positive TAB, and more likely to relapse. ARB therapy prior to diagnosis showed an association with success at discontinuing glucocorticoids. Statin therapy did not alter the clinical presentation or course of GCA.

Antidepressant properties of Centella asciatica (L.) (takip-kuhol): an experimental study on mice model

Filipino traditional healers have been using Centella asciatica (L.), locally known as "takip-kuhol", as a stimulant and brain tonic. Coloma et al found its leaf decoction comparable to Fluoxetine in decreasing immobility time in mice with induced depression. Objectives: This study was then conceived to establish antidepressant properties of Centella asciatica (L.) (takip-kuhol) leaf extract in a mice model using a systematic purification of leaf extract and comparing it with Fluoxetine, a known antidepressant. Method: This is a single blind experimental study using completely randomized design wherein Centella asciatica (L.) (takip-kuhol) leaves were percolated in 60 percent ethanol, then evaporated to extract a purified form. Effective antidepressant dose50 (ED50) was determined using the Forced-swimming test. Centella asciatica (L.) (takip-kuhol) ED50 was then compared with Fluoxetine 10 mg/kg and NSS 0.1 ml. to establish antidepressant properties through measurement of immobility time in the Forced-swimming test. ED50 of Centella asciatica (L.) (takip-kuhol) was found to be 37.8 mg/kg. Results: It was noted to be statistically comparable to Fluoxetine 10 mg/kg in improving immobility time at t0.05 of 2.101 and F0.05 of 3.39 (t=0.24 and F=0.09). Both Fluoxetine 10 mg/kg and Centella asciatica (L.) (takip-kuhol) 37.8 mg/kg were found to be statistically not comparable to NSS 0.1 ml at these levels (t=3.89 and 4.97, respectively and F=14.72 and 17.11, respectively). Conclusion: Hence this study concludes that Centella asciatica (L.) (takip-kuhol) has comparable antidepressant properties as Fluoxetine 10 mg/kg in mice, and is better than placebo in improving induced depression.