Vasorin-deficient mice display disturbed vitamin D and mineral homeostasis in combination with a low bone mass phenotype.

Vasorin (Vasn) is a pleiotropic molecule involved in various physiological and pathological conditions, including cancer. Vasn has also been detected in bone cells of developing skeletal tissues but no function for Vasn in bone metabolism has been implicated yet. Therefore, this study aimed to investigate if Vasn plays a significant role in bone biology.

Inhibition of hypoxia-induced Mucin 1 alters the proteomic composition of human osteoblast-produced extracellular matrix, leading to reduced osteogenic and angiogenic potential.

The bone microenvironment is one of the most hypoxic regions of the human body and in experimental models; hypoxia inhibits osteogenic differentiation of mesenchymal stromal cells (MSCs). Our previous work revealed that Mucin 1 (MUC1) was dynamically expressed during osteogenic differentiation of human MSCs and upregulated by hypoxia. Upon stimulation, its C-terminus (MUC1-CT) is proteolytically cleaved, translocases to the nucleus, and binds to promoters of target genes.

Identification of osteolineage cell-derived extracellular vesicle cargo implicated in hematopoietic support.

Osteolineage cell-derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non-stimulatory osteolineage EVs by next-generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV-derived candidate regulators of ex vivo HSPC expansion.

Mucin 1 (Muc1) Deficiency in Female Mice Leads to Temporal Skeletal Changes During Aging.

Mucin1 (MUC1) encodes a glycoprotein that has been demonstrated to have important roles in cell-cell interactions, cell-matrix interactions, cell signaling, modulating tumor progression and metastasis, and providing physical protection to cells against pathogens. In this study, we investigated the bone phenotype in female C57BL/6 null mice and the impact of the loss of on osteoblasts and osteoclasts. We found that deletion of results in reduced trabecular bone volume in 8-week-old mice compared with wild-type controls, but the trabecular bone volume fraction normalizes with increasing age.

Human mesenchymal stromal cells in adhesion to cell-derived extracellular matrix and titanium: Comparative kinome profile analysis.

The extracellular matrix (ECM) physically supports cells and influences stem cell behaviour, modulating kinase-mediated signalling cascades. Cell-derived ECMs have emerged in bone regeneration as they reproduce physiological tissue-architecture and ameliorate mesenchymal stromal cell (MSC) properties. Titanium scaffolds show good mechanical properties, facilitate cell adhesion, and have been routinely used for bone tissue engineering (BTE).

Collagen I derived recombinant protein microspheres as novel delivery vehicles for bone morphogenetic protein-2.

Bone morphogenetic protein-2 (BMP-2) is a powerful osteoinductive protein; however, there is a need for the development of a safe and efficient BMP-2 release system for bone regeneration therapies. Recombinant extracellular matrix proteins are promising next generation biomaterials since the proteins are well-defined, reproducible and can be tailored for specific applications. In this study, we have developed a novel and versatile BMP-2 delivery system using microspheres from a recombinant protein based on human collagen I (RCP).

Understanding Age-Induced Cortical Porosity in Women: The Accumulation and Coalescence of Eroded Cavities Upon Existing Intracortical Canals Is the Main Contributor.

Intracortical bone remodeling normally ensures maintenance of the cortical bone matrix and strength, but during aging, this remodeling generates excessive porosity. The mechanism behind the age-induced cortical porosity is poorly understood and addressed in the present study. This study consists of a histomorphometric analysis of sections of iliac bone specimens from 35 women (age 16-78 years).

Identification of Chloride Intracellular Channel Protein 3 as a Novel Gene Affecting Human Bone Formation.

Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. The bone building cells, osteoblasts, are derived from mesenchymal stromal cells (MSCs); however, with increasing age osteogenic differentiation is diminished and more adipocytes are seen in the bone marrow, suggesting a shift in MSC lineage commitment. Identification of specific factors that stimulate osteoblast differentiation from human MSCs may deliver therapeutic targets to treat osteoporosis.

Molecular characterization of human osteoblast-derived extracellular vesicle mRNA using next-generation sequencing.

Extracellular vesicles (EVs) are membrane-bound intercellular communication vehicles that transport proteins, lipids and nucleic acids with regulatory capacity between cells. RNA profiling using microarrays and sequencing technologies has revolutionized the discovery of EV-RNA content, which is crucial to understand the molecular mechanism of EV function. Recent studies have indicated that EVs are enriched with specific RNAs compared to the originating cells suggestive of an active sorting mechanism.

Identification of Three Early Phases of Cell-Fate Determination during Osteogenic and Adipogenic Differentiation by Transcription Factor Dynamics.

Age-related skeletal degeneration in patients with osteoporosis is characterized by decreased bone mass and occurs concomitant with an increase in bone marrow adipocytes. Using microarray expression profiling with high temporal resolution, we identified gene regulatory events in early stages of osteogenic and adipogenic lineage commitment of human mesenchymal stromal cells (hMSCs). Data analysis revealed three distinct phases when cells adopt a committed expression phenotype: initiation of differentiation (0-3 hr, phase I), lineage acquisition (6-24 hr, phase II), and early lineage progression (48-96 hr, phase III).

Comparative proteomic profiling of human osteoblast-derived extracellular matrices identifies proteins involved in mesenchymal stromal cell osteogenic differentiation and mineralization.

The extracellular matrix (ECM) is a dynamic component of tissue architecture that physically supports cells and actively influences their behavior. In the context of bone regeneration, cell-secreted ECMs have become of interest as they reproduce tissue-architecture and modulate the promising properties of mesenchymal stem cells (MSCs). We have previously created an in vitro model of human osteoblast-derived devitalized ECM that was osteopromotive for MSCs.

Serum Phosphate Is Associated With Fracture Risk: The Rotterdam Study and MrOS.

Extreme phosphate levels (P) have been associated with mineralization defects and increased fracture risk. Whether P within normal range is related to bone health in the general population is not well understood. To investigate the association of P with bone mineral density (BMD) and fracture risk, we assessed two population-based cohorts: the Dutch Rotterdam Study (RS-I, RS-II, RS-III; n = 6791) and the US Osteoporotic Fractures in Men (MrOS; n = 5425) study.

Osteoblasts secrete miRNA-containing extracellular vesicles that enhance expansion of human umbilical cord blood cells.

Osteolineage cells represent one of the critical bone marrow niche components that support maintenance of hematopoietic stem and progenitor cells (HSPCs). Recent studies demonstrate that extracellular vesicles (EVs) regulate stem cell development via horizontal transfer of bioactive cargo, including microRNAs (miRNAs). Using next-generation sequencing we show that human osteoblast-derived EVs contain highly abundant miRNAs specifically enriched in EVs, including critical regulators of hematopoietic proliferation (e.

Paracrine Signaling by Extracellular Vesicles via Osteoblasts.

Extracellular vesicles (EVs), spherical bilayered proteolipids, behave as paracrine effectors since they are released from cells to deliver signals to other cells. They control a diverse range of biological processes by transferring proteins, lipids, and nucleic acids between cells and are secreted by a wide spectrum of cell types and are found in various biological fluids. EVs are formed at the plasma membrane or in endosomes and are heterogeneous in size and composition.

Novel Compound Heterozygous Mutations in the CYP27B1 Gene Lead to Pseudovitamin D-Deficient Rickets.

Pseudovitamin D deficiency is the consequence of a genetic defect in the CYP27B1 gene resulting in diminished or absent conversion of 25-hydroxyvitamin D3 (25-(OH)D3) into 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and leads to growth retardation and rickets, usually in the first 2 years of life. DNA obtained from human leucocytes from a patient suspected of pseudovitamin D deficiency and her healthy parents was sequenced for a genetic defect in the CYP27B1 gene. In silico analyses on the mutations were performed using online available software.

Lifelong challenge of calcium homeostasis in male mice lacking TRPV5 leads to changes in bone and calcium metabolism.

Trpv5 plays an important role in calcium (Ca2+) homeostasis, among others by mediating renal calcium reabsorption. Accordingly, Trpv5 deficiency strongly stresses Ca2+ homeostasis in order to maintain stable serum Ca2+. We addressed the impact of lifelong challenge of calcium homeostasis on the bone phenotype of these mice.

THE INFLUENCE OF ULTRAVIOLET-B RADIATION ON THE GROWTH OF MARABOU STORK (LEPTOPTILOS CRUMENIFERUS) NESTLINGS IN RELATION TO PLASMA CALCIUM, PHOSPHORUS, AND VITAMIN D3 CONCENTRATIONS.

In order to prevent metabolic bone disease in growing captive-bred marabou storks (Leptoptilos crumeniferus), three hatchlings were exposed twice a day for 30 min each time to ultraviolet-B (UVB) radiation. During their first 35 days of life, body weights were monitored weekly, and blood was collected to determine total calcium, phosphorus, 25(OH) cholecalciferol, and 1.25(OH)₂cholecalciferol plasma levels.

25-Hydroxyvitamin D and osteoarthritis: A meta-analysis including new data.

Objectives: To study the relationship between 25-hydroxy (OH) vitamin D serum levels and osteoarthritis (OA) of the knee, hip, and hand in a meta-analysis, with updated and expanded results of our previous study.

Methods: Pubmed was searched from February 1975 to December 2014 for articles assessing the relationship between vitamin D levels and OA. In our meta-analysis, 6 cross-sectional and 6 longitudinal studies were included.

Supporting data of spatiotemporal proliferation of human stromal cells adjusts to nutrient availability and leads to stanniocalcin-1 expression in vitro and in vivo.

This data article contains seven figures and two tables supporting the research article entitled: spatiotemporal proliferation of human stromal cells adjusts to nutrient availability and leads to stanniocalcin-1 expression in vitro and in vivo[1]. The data explain the culture of stromal cells in vitro in three culture systems: discs, scaffolds and scaffolds in a perfusion bioreactor system. Also, quantification of extracellular matrix components (ECM) in vitro and staining of ECM components in vivo can be found here.

Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway.

Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. In this study, we have identified pathways that stimulate differentiation of bone forming osteoblasts from human mesenchymal stromal cells (hMSCs). Gene expression profiling was performed in hMSCs differentiated toward osteoblasts (at 6 h).

Spatiotemporal proliferation of human stromal cells adjusts to nutrient availability and leads to stanniocalcin-1 expression in vitro and in vivo.

Cells and tissues are intrinsically adapted to molecular gradients and use them to maintain or change their activity. The effect of such gradients is particularly important for cell populations that have an intrinsic capacity to differentiate into multiple cell lineages, such as bone marrow derived mesenchymal stromal cells (MSCs). Our results showed that nutrient gradients prompt the spatiotemporal organization of MSCs in 3D culture.

Dexamethasone in osteogenic medium strongly induces adipocyte differentiation of mouse bone marrow stromal cells and increases osteoblast differentiation.

Background: Osteoblasts and adipocytes share a common mesenchymal stem cell origin. Therefore, it has been suggested that the accumulation of marrow adipocytes observed in bone loss is caused by a shift in the commitment of mesenchymal stem cells from the osteogenic pathway to the adipogenic pathway. Supporting this hypothesis the competition between adipogenic and osteogenic lineages was widely demonstrated on partially homogeneous cell populations.

Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio.

Thrombin and its receptor (TR) are, respectively, expressed in osteoclasts and osteoblasts. However, their physiological roles on bone metabolism have not been fully elucidated. Here we investigated the bone microarchitecture by micro-computed tomography (μCT) and demonstrated increased trabecular and cortical bone mass in femurs of TR KO mice compared to WT littermates.

Calcifying vascular smooth muscle cells and osteoblasts: independent cell types exhibiting extracellular matrix and biomineralization-related mimicries.

Background: Ectopic vascular calcifications represent a major clinical problem associated with cardiovascular disease and mortality. However, the mechanisms underlying pathological vascular calcifications are largely unknown hampering the development of therapies to tackle this life threatening medical condition.

Results: In order to gain insight into the genes and mechanisms driving this pathological calcification process we analyzed the transcriptional profile of calcifying vascular smooth muscle cells (C-VSMCs).

Proteomic signatures of extracellular vesicles secreted by nonmineralizing and mineralizing human osteoblasts and stimulation of tumor cell growth.

Beyond forming bone, osteoblasts play pivotal roles in various biologic processes, including hematopoiesis and bone metastasis. Extracellular vesicles (EVs) have been implicated in intercellular communication via transfer of proteins and nucleic acids between cells. We focused on the proteomic characterization of nonmineralizing (NMOBs) and mineralizing (MOBs) human osteoblast (SV-HFOs) EVs and investigated their effect on human prostate cancer (PC3) cells by microscopic, proteomic, and gene expression analyses.