A novel chemical chaperone ameliorates osteoblast homeostasis and extracellular matrix in osteogenesis imperfecta.

Aims: Osteogenesis imperfecta (OI) is a collagen I-related heritable family of skeletal diseases associated to extreme bone fragility and deformity. Its classical forms are caused by dominant mutations in COL1A1 and COL1A2, which encode for the protein α chains, and are characterized by impairment in collagen I structure, folding, and secretion. Mutant collagen I assembles in an altered extracellular matrix affecting mineralization and bone properties and partially accumulating inside the cells, leading to impaired trafficking and cellular stress.

Zebrafish Models for Skeletal and Extraskeletal Osteogenesis Imperfecta Features: Unveiling Pathophysiology and Paving the Way for Drug Discovery.

In the last decades, the easy genetic manipulation, the external fertilization, the high percentage of homology with human genes and the reduced husbandry costs compared to rodents, made zebrafish a valid model for studying human diseases and for developing new therapeutical strategies. Since zebrafish shares with mammals the same bone cells and ossification types, it became widely used to dissect mechanisms and possible new therapeutic approaches in the field of common and rare bone diseases, such as osteoporosis and osteogenesis imperfecta (OI), respectively. OI is a heritable skeletal disorder caused by defects in gene encoding collagen I or proteins/enzymes necessary for collagen I synthesis and secretion.

Sestrin2 drives ER-phagy in response to protein misfolding.

Protein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation.

Matrix first, minerals later: fine-tuned dietary phosphate increases bone formation in zebrafish.

Bone matrix formation and mineralization are two closely related, yet separated processes. Matrix formation occurs first, mineralization is a second step strictly dependent on the dietary intake of calcium and phosphorus (P). However, mineralization is commonly used as diagnostic parameter for bone-related diseases.

Cell differentiation and matrix organization are differentially affected during bone formation in osteogenesis imperfecta zebrafish models with different genetic defects impacting collagen type I structure.

Osteogenesis imperfecta (OI) is a family of rare heritable skeletal disorders associated with dominant mutations in the collagen type I encoding genes and recessive defects in proteins involved in collagen type I synthesis and processing and in osteoblast differentiation and activity. Historically, it was believed that the OI bone phenotype was only caused by abnormal collagen type I fibrils in the extracellular matrix, but more recently it became clear that the altered bone cell homeostasis, due to mutant collagen retention, plays a relevant role in modulating disease severity in most of the OI forms and it is correlated to impaired bone cell differentiation. Despite in vitro evidence, in vivo data are missing.

TAPT1-at the crossroads of extracellular matrix and signaling in Osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a hereditary skeletal disorder primarily affecting collagen type I structure and function, causing bone fragility and occasionally versatile extraskeletal symptoms. This study expands the spectrum of OI-causing TAPT1 mutations and links extracellular matrix changes to signaling regulation.

Outer Membrane Vesicles (OMVs) as Biomedical Tools and Their Relevance as Immune-Modulating Agents against Infections: Current Status and Future Prospects.

Outer membrane vesicles (OMVs) are lipid-membrane-bounded nanoparticles that are released from Gram-negative bacteria via vesiculation of the outer membrane. They have vital roles in different biological processes and recently, they have received increasing attention as possible candidates for a broad variety of biomedical applications. In particular, OMVs have several characteristics that enable them to be promising candidates for immune modulation against pathogens, such as their ability to induce the host immune responses given their resemblance to the parental bacterial cell.

Zebrafish Tric-b is required for skeletal development and bone cells differentiation.

Introduction: Trimeric intracellular potassium channels TRIC-A and -B are endoplasmic reticulum (ER) integral membrane proteins, involved in the regulation of calcium release mediated by ryanodine (RyRs) and inositol 1,4,5-trisphosphate (IPRs) receptors, respectively. While TRIC-A is mainly expressed in excitable cells, TRIC-B is ubiquitously distributed at moderate level. TRIC-B deficiency causes a dysregulation of calcium flux from the ER, which impacts on multiple collagen specific chaperones and modifying enzymatic activity, leading to a rare form of osteogenesis imperfecta (OI Type XIV).

Structure, evolution and expression of zebrafish cartilage oligomeric matrix protein (COMP, TSP5). CRISPR-Cas mutants show a dominant phenotype in myosepta.

COMP (Cartilage Oligomeric Matrix Protein), also named thrombospondin-5, is a member of the thrombospondin family of extracellular matrix proteins. It is of clinical relevance, as in humans mutations in COMP lead to chondrodysplasias. The gene encoding zebrafish Comp is located on chromosome 11 in synteny with its mammalian orthologs.

The Highly Efficient Expression System of Recombinant Human Prolidase and the Effect of N-Terminal His-Tag on the Enzyme Activity.

Prolidase is an enzyme hydrolyzing dipeptides containing proline or hydroxyprolineat the C-terminus and plays an important role in collagen turnover. Human prolidase is active as a dimer with the C-terminal domain containing two Mn ions in its active site. The study aimed to develop a highly efficient expression system of recombinant human prolidase (rhPEPD) and to evaluate the effect of the N-terminal His-Tag on its enzymatic and biological activity.

Dissecting the phenotypic variability of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous family of collagen type I-related diseases characterized by bone fragility. OI is most commonly caused by single-nucleotide substitutions that replace glycine residues or exon splicing defects in the COL1A1 and COL1A2 genes that encode the α1(I) and α2(I) collagen chains. Mutant collagen is partially retained intracellularly, impairing cell homeostasis.

Recombinant Prolidase Activates EGFR-Dependent Cell Growth in an Experimental Model of Inflammation in HaCaT Keratinocytes. Implication for Wound Healing.

This study was conducted to investigate the proliferative capacity of recombinant human prolidase (rhPEPD) in a human model of inflammation induced by IL-1 in HaCaT keratinocytes. In this report, we provide evidence that IL-1 stimulates keratinocyte proliferation, and rhPEPD significantly augmented this process through activation of epidermal growth factor receptor (EGFR) and downstream signaling proteins as phosphorylated Akt, ERK1/2, and STAT3, which are implicated in keratinocyte migration, proliferation, and epithelialization during the wound healing process. Inhibition of PEPD-dependent EGFR signaling by gefitinib supported the finding.

Compression Fractures and Partial Phenotype Rescue With a Low Phosphorus Diet in the Zebrafish Osteogenesis Imperfecta Model.

Osteogenesis imperfecta (OI) is a group of heritable disorders affecting bone and other connective tissues. Dominant OI forms are mainly caused by mutations in collagen type I. Patients suffer from skeletal deformities, fractures of long bones and vertebral compression fractures from early childhood onward.

Understanding the Role of Estrogen Receptor Status in PRODH/POX-Dependent Apoptosis/Survival in Breast Cancer Cells.

It has been suggested that activation of estrogen receptor α (ER α) stimulates cell proliferation. In contrast, estrogen receptor β (ER β) has anti-proliferative and pro-apoptotic activity. Although the role of estrogens in estrogen receptor-positive breast cancer progression has been well established, the mechanism of their effect on apoptosis is not fully understood.

Knocking out TMEM38B in human foetal osteoblasts hFOB 1.19 by CRISPR/Cas9: A model for recessive OI type XIV.

Osteogenesis imperfecta (OI) type XIV is a rare recessive bone disorder characterized by variable degree of severity associated to osteopenia. It is caused by mutations in TMEM38B encoding for the trimeric intracellular cation channel TRIC-B, specific for potassium and ubiquitously present in the endoplasmic reticulum (ER) membrane. OI type XIV molecular basis is largely unknown and, due to the rarity of the disease, the availability of patients' osteoblasts is challenging.

Phenotypic Characterization of Immortalized Chondrocytes from a Desbuquois Dysplasia Type 1 Mouse Model: A Tool for Studying Defects in Glycosaminoglycan Biosynthesis.

The complexity of skeletal pathologies makes use of in vivo models essential to elucidate the pathogenesis of the diseases; nevertheless, chondrocyte and osteoblast cell lines provide relevant information on the underlying disease mechanisms. Due to the limitations of primary chondrocytes, immortalized cells represent a unique tool to overcome this problem since they grow very easily for several passages. However, in the immortalization procedure the cells might lose the original phenotype; thus, these cell lines should be deeply characterized before their use.

The Stimulating Effect of Rosmarinic Acid and Extracts from Rosemary and Lemon Balm on Collagen Type I Biosynthesis in Osteogenesis Imperfecta Type I Skin Fibroblasts.

Rosemary extract (RE) and lemon balm extract (LBE) attract particular attention of pharmacists due to their high therapeutic potential. Osteogenesis imperfecta (OI) type I is a heritable disease caused by mutations in type I collagen and characterized by its reduced amount. The aim of the study was to evaluate the effect of the extracts and rosmarinic acid (RA) on collagen type I level in OI skin fibroblasts.