No abstract

Regulation of food intake is a recently identified endocrine function of bone that is mediated by Lipocalin-2 (LCN2). Osteoblast-secreted LCN2 suppresses appetite and decreases fat mass while improving glucose metabolism. We now show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in obese mice and obese, prediabetic women. However, LCN2 serum levels also correlate with body mass index and insulin resistance in the same individuals and are increased in obese mice. To dissect this apparent discrepancy, we modulated LCN2 levels in mice. Silencing Lcn2 expression worsens metabolic dysfunction in genetic and diet-induced obese mice. Conversely, increasing circulating LCN2 levels improves metabolic parameters and promotes β-cell function in mouse models of β-cell failure acting as a growth factor necessary for β-cell adaptation to higher metabolic load. These results indicate that LCN2 up-regulation is a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.

The objective of the present study was to examine the effect of dairy products enriched with calcium, vitamin D(3), and phylloquinone (vitamin K(1)) or menaquinone-7 (vitamin K(2)) on parameters of bone metabolism in postmenopausal women following a 12-month intervention. Postmenopausal women were divided into three intervention groups and a control group (CG). All three intervention groups attended biweekly sessions and received fortified dairy products providing daily 800 mg of calcium and 10 μg of vitamin D(3) (CaD). Furthermore, in two of the three intervention groups the dairy products were also enriched with vitamin K, providing daily 100 μg of either phylloquinone (CaDK1) or menaquinone-7 (CaDK2). The increase observed for serum 25(OH)D levels in all intervention groups and the increase observed for serum IGF-I levels in the CaDK2 group differed significantly compared to the changes observed in CG (P = 0.010 and P = 0.028, respectively). Furthermore, both the CaDK1 and CaDK2 groups had a significantly lower mean serum undercarboxylated osteocalcin to osteocalcin ratio and urine deoxypyridinoline levels at follow-up compared to the CaD and CG groups (P = 0.001 and P = 0.047, respectively). Significant increases in total-body BMD were observed in all intervention groups compared to CG (P < 0.05), while significant increases in lumbar spine BMD were observed only for CaDK1 and CaDK2 compared to CG (P < 0.05) after controlling for changes in serum 25(OH)D levels and dietary calcium intake. In conclusion, the present study revealed more favorable changes in bone metabolism and bone mass indices for the two vitamin K-supplemented groups, mainly reflected in the suppression of serum levels of bone remodeling indices and in the more positive changes in lumbar spine BMD for these two study groups.

SummaryThe aim of this study was to examine the levels of endoplasmic reticulum (ER) stress in minor salivary glands, to investigate the interplay between ER stress-induced autophagy and apoptosis in human salivary gland (HSG) cells and to test the effect of ER stress-induced apoptosis on the cellular redistribution of the two major Sj€ ogren's syndrome (SS) autoantigens Ro/ Sj€ ogren's syndrome-related antigen A (SSA) and La/Sj€ ogren's syndromerelated antigen B (SSB). Minor salivary gland biopsies from SS patients and sicca controls were examined by immunohistochemistry for the expression of 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) as an indicator of unfolded protein response (UPR). HSG cells were treated with thapsigargin (TG) and cell viability, autophagy and apoptosis were assessed. Immunoblot was applied to detect the conversion of LC3I to LC3II and the protein levels of GRP78/BiP and X-box binding protein-1 (XBP-1). Apoptosis was evaluated by a single-stranded DNA enzyme-linked immunosorbent assay (ELISA). Ro/SSA and La/SSB localization was visualized using immunofluorescence. GRP78/BiP was expressed by acinar and ductal epithelial cells in salivary glands of patients and sicca controls. TG treatment induced autophagy, as indicated by enhanced protein expression of LC3II. The protein levels of UPR marker XBP-1 were increased after TG treatment, while GRP78/BiP levels were decreased. TG treatment resulted in induction of HSG apoptosis. Ro/SSA and La/SSB autoantigens were localized predominantly to the cytoplasm in resting cells, while they were redistributed to cell membrane and blebs in the apoptotic cells. In conclusion, ER stress is activated in minor salivary gland epithelial cells from SS patients and controls. ER stress-induced apoptosis in HSG cells leads to cell surface and apoptotic blebs relocalization of Ro/SSA and La/SSB autoantigens.

Bone is the most frequent site of metastases of prostate cancer and is almost always the first and frequently the only site of metastases where disease will progress to stage D3. In addition, the number of skeletal metastatic foci is the most powerful independent prognostic factor of limited response to hormone ablation therapy and poor survival of patients with advanced prostate cancer. Furthermore, disease progression frequently occurs in the osteoblastic metastases, even though androgen ablation therapy still provides adequate and sustained control of disease at the primary site. Notably, the management of metastatic disease onto bones has traditionally relied on therapeutic modalities, which almost exclusively aim at directly inducing cancer cell death. However, accumulating pieces of evidence, from both the clinical and the basic research front, point to major limitations of this conventional approach. The in vivo response of malignant cells to anticancer therapies is directly influenced by the local microenvironment in which they metastasize. In particular, organ sites frequently involved in metastatic diseases, such as the bones, appear to confer to metastatic cells protection from anticancer drug-induced apoptosis. This protection is mediated by soluble growth factors and cytokines released by the normal cellular constituents of the host tissue microenvironment. The characterization of bone microenvironment-related survival factors has led to the development of a novel hormone manipulation which can re-introduce clinical responses in patients with stage D3 prostate cancer.