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Articular cartilage lacks an intrinsic repair capacity and due to the ability of mesenchymal stem cells (MSCs) to differentiate into chondrocytes, MSCs have been touted as a cellular source to regenerate damaged cartilage. However, a number of prevailing concerns for such a treatment remain. Generally, administration of MSCs into a cartilage defect results in poor regeneration of the damaged cartilage with the repaired cartilage consisting primarily of fibro-cartilage rather than hyaline cartilage. Methods that improve the chondrogenic potential of transplanted MSCs in vivo may be advantageous. In addition, the proclivity of MSC-derived cartilage to undergo hypertrophic differentiation or form bone in vivo also remains a clinical concern. If MSC-derived cartilage was to undergo hypertrophic differentiation in vivo, this would be deleterious in a clinical setting. This study focuses on establishing a mechanism of action by which hypoxia or low oxygen tension can be used to both enhance chondrogenesis and attenuate hypertrophic differentiation of both MSC and ATDC5 derived chondrocytes. Having elucidated a novel mechanism of action, the subsequent goals of this study were to develop an in vitro culture regime to mimic the beneficial effects of physiological low oxygen tension in a normoxic environment.

Purpose Review calcium homeostasis in pregnancy and provide evidence-based best practice recommendations for the management of hypoparathyroidism in pregnancy. Methods We searched MEDLINE, EMBASE and Cochrane databases from January 2000 to April 1, 2018. A total of 65 articles were included in the final review. Conclusions During pregnancy, calcitriol levels increase by two- to-three-fold resulting in enhanced intestinal calcium absorption. The renal filtered calcium load increases leading to hypercalciuria. PTHrP production by the placenta and breasts increases by three-fold, and this may lower the doses of calcium and calcitriol required during pregnancy in mothers with hypoparathyroidism. The literature however describes a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, with some women requiring higher doses of calcitriol, whereas others require lower doses. Close monitoring is necessary as hypercalcemia in the mother may suppress the fetal parathyroid gland development. Also hypocalcemia in the mother is harmful as it may result in secondary hyperparathyroidism in the fetus. This may be associated with demineralization of the fetal skeleton and the development of intrauterine fractures. Inadequate treatment of hypoparathyroidism may also result in uterine contractions and an increased risk of miscarriage. Treatment targets during pregnancy are to maintain a low normal serum calcium. Calcium, calcitriol and vitamin D supplements are safe during pregnancy. Close monitoring of the mother with a multidisciplinary team is advised for optimal care. If calcium homeostasis is well controlled during pregnancy, most women with hypoparathyroidism have an uncomplicated pregnancy and give birth to healthy babies.

8 pages, 1 table, 1 figure, Glucocorticoids (GCs) are the final effector products of a neuroendocrine HPA/HPI axis governing energy balance and stress response in vertebrates. From a physiological point of view, basal GC levels are essential for intermediary metabolism and participate in the development and homeostasis of a wide range of body tissues, including the skeleton. Numerous mammalian studies have demonstrated that GC hormones exert a positive role during bone modeling and remodeling as they promote osteoblastogenesis to maintain the bone architecture. Although the pharmacological effect of the so-called stress hormones has been widely reported, the role of endogenous GCs on bone mineral metabolism as result of the endocrine stress response has been largely overlooked across vertebrates. In addition, stress responses are variable depending on the stressor (e.g., starvation, predation, and environmental change), life cycle events (e.g., migration and aging), and differ among vertebrate lineages, which react differently according to their biological, social and cognitive complexity (e.g., mineral demands, physical, and psychological stress). This review intends to summarize the endogenous GCs action on bone metabolism of mammals and fish under a variety of challenging circumstances. Particular emphasis will be given to the regulatory loop between GCs and the parathyroid hormone (PTH) family peptides, and other key regulators of mineral homeostasis and bone remodeling in vertebrates., This work was funded by the Spanish Economy and Competitiveness Ministry projects AGL2014-52473R and AGL2017-89648P to JR. PS-B was supported by AGL2014-52473R and AGL2017-89648P project contracts. PG acknowledges the Portuguese Foundation for Science and Technology (project grant PTDC/BIA-ANM/4225/2012).

In marine fish, high epithelial intestinal HCO3- secretion generates luminal carbonate precipitates of divalent cations that play a key role in water and ion homeostasis. The present study was designed to expose the putative role for calcium and the calcium-sensing receptor (CaSR) in the regulation of HCO3- secretion in the intestine of the sea bream (Sparus aurata L.). Effects on the expression of the CaSR in the intestine were evaluated by qPCR and an increase was observed in the anterior intestine in fed fish compared with unfed fish and with different regions of intestine. CaSR expression reflected intestinal fluid calcium concentration. In addition, anterior intestine tissue was mounted in Ussing chambers to test the putative regulation of HCO3- secretion in vitro using the anterior intestine. HCO3- secretion was sensitive to varying calcium levels in luminal saline and to calcimimetic compounds known to activate/block the CaSR i.e., R 568 and NPS-2143. Subsequent experiments were performed in intestinal sacs to measure water absorption and the sensitivity of water absorption to varying luminal levels of calcium and calcimimetics were exposed as well. It appears, that CaSR mediates HCO3- secretion and water absorption in marine fish as shown by responsiveness to calcium levels and calcimimetic compounds. European Social Funds through the Portuguese National Science Foundation (FCT) [SFRH/BD/113363/2015, PTDC/MAR-BIO/3034/2014]; Portuguese Foundation for Science and Technology (FCT) [UID/Multi/04326/2013]; Ministry of Science and Higher Education

Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed