169,825 research outputs found
The RANKL-RANK axis: A bone to thymus round trip
No full textThe identification of Receptor activator of nuclear factor kappa B ligand (RANKL) and its cognate receptor Receptor activator of nuclear factor kappa B (RANK) during a search for novel tumor necrosis factor receptor (TNFR) superfamily members has dramatically changed the scenario of bone biology by providing the functional and biochemical proof that RANKL signaling via RANK is the master factor for osteoclastogenesis. In parallel, two independent studies reported the identification of mouse RANKL on activated T cells and of a ligand for osteoprotegerin on a murine bone marrow-derived stromal cell line. After these seminal findings, accumulating data indicated RANKL and RANK not only as essential players for the development and activation of osteoclasts, but also for the correct differentiation of medullary thymic epithelial cells (mTECs) that act as mediators of the central tolerance process by which self-reactive T cells are eliminated while regulatory T cells are generated. In light of the RANKL-RANK multi-task function, an antibody targeting this pathway, denosumab, is now commonly used in the therapy of bone loss diseases including chronic inflammatory bone disorders and osteolytic bone metastases; furthermore, preclinical data support the therapeutic application of denosumab in the framework of a broader spectrum of tumors. Here, we discuss advances in cellular and molecular mechanisms elicited by RANKL-RANK pathway in the bone and thymus, and the extent to which its inhibition or augmentation can be translated in the clinical arena
Genetics of Osteopetrosis
No full textPurpose of Review: The term osteopetrosis refers to a group of rare skeletal diseases sharing the hallmark of a generalized increase in bone density owing to a defect in bone resorption. Osteopetrosis is clinically and genetically heterogeneous, and a precise molecular classification is relevant for prognosis and treatment. Here, we review recent data on the pathogenesis of this disorder. Recent Findings: Novel mutations in known genes as well as defects in new genes have been recently reported, further expanding the spectrum of molecular defects leading to osteopetrosis. Summary: Exploitation of next-generation sequencing tools is ever spreading, facilitating differential diagnosis. Some complex phenotypes in which osteopetrosis is accompanied by additional clinical features have received a molecular classification, also involving new genes. Moreover, novel types of mutations have been recognized, which for their nature or genomic location are at high risk being neglected. Yet, the causative mutation is unknown in some patients, indicating that the genetics of osteopetrosis still deserves intense research efforts
Soluble factors on stage to direct mesenchymal stem cells fate
No full textMesenchymal stem cells (MSCs) are multipotent stromal cells that are identified by in vitro plastic adherence, colony-forming capacity, expression of a panel of surface molecules, and ability to differentiate at least toward osteogenic, adipogenic, and chondrogenic lineages. They also produce trophic factors with immunomodulatory, proangiogenic, and antiapoptotic functions influencing the behavior of neighboring cells. On the other hand, a reciprocal regulation takes place; in fact, MSCs can be isolated from several tissues, and depending on the original microenvironment and the range of stimuli received from there, they can display differences in their essential characteristics. Here, we focus mainly on the bone tissue and how soluble factors, such as growth factors, cytokines, and hormones, present in this microenvironment can orchestrate bone marrow-derived MSCs fate. We also briefly describe the alteration of MSCs behavior in pathological settings such as hematological cancer, bone metastasis, and bone marrow failure syndromes. Overall, the possibility to modulate MSCs plasticity makes them an attractive tool for diverse applications of tissue regeneration in cell therapy. Therefore, the comprehensive understanding of the microenvironment characteristics and components better suited to obtain a specific MSCs response can be extremely useful for clinical use
V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations
No full textSevere combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the HAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone. (C) 2001 by The American Society of Hematology
A common central engine for long gamma-ray bursts and Type Ib/c supernovae
No full textLong-duration, spectrally soft gamma-ray bursts (GRBs) are associated with Type Ic core collapse (CC) supernovae (SNe), and thus arise from the death of massive stars. In the collapsar model, the jet launched by the central engine must bore its way out of the progenitor star before it can produce a GRB. Most of these jets do not break out, and are instead 'choked' inside the star, as the central engine activity time, t(e), is not long enough. Modelling the long-soft GRB duration distribution assuming a power-law distribution for their central engine activity times, proportional to t(e)(-alpha) for t(e) > t(b), we find a steep distribution (alpha similar to 4) and a typical GRB jet breakout time of t(b) similar to 60s in the star's frame. The latter suggests the presence of a low-density, extended envelope surrounding the progenitor star, similar to that previously inferred for low-luminosity GRBs. Extrapolating the range of validity of this power law below what is directly observable, to t(e) < t(b), by only a factor of similar to 4-5 produces enough events to account for all Type Ib/c SNe. Such extrapolation is necessary to avoid fine-tuning the distribution of central engine activity times with the breakout time, which are presumably unrelated. We speculate that central engines launching relativistic jets may operate in all Type Ib/c SNe. In this case, the existence of a common central engine would imply that (i) the jet may significantly contribute to the energy of the SN; (ii) various observational signatures, like the asphericity of the explosion, could be directly related to jet's interaction with the star
Infantile malignant, autosomal recessive osteopetrosis : the rich and the poor
No full textHuman recessive osteopetrosis (ARO) represents a group of diseases in which, due to a defect in osteoclasts, bone resorption is prevented. The deficit could arise either from failure in osteoclast differentiation or from inability to perform resorption by mature, multinucleated, but nonfunctional cells. Historically, osteopetrosis due to both these mechanisms was found in spontaneous and artificially created mouse mutants, but the first five genes identified in human ARO (CA-II, TCIRG1, ClCN7, OSTM1, and PLEKHM1) were all involved in the effector function of mature osteoclasts, being linked to acidification of the cell/bone interface or to intracellular processing of the resorbed material. Differentiation defects in human ARO have only recently been described, following the identification of mutations in both RANKL and RANK, which define a new form of osteoclast-poor ARO, as expected from biochemical, cellular, and animal studies. The molecular dissection of ARO has prognostic and therapeutic implications. RANKL-dependent patients, in particular, represent an interesting subset which could benefit from mesenchymal cell transplant and/or administration of soluble RANKL cytokine
Of Omenn and mice
No full textOmenn syndrome (OS) is a peculiar immunodeficiency in which profound T and B cell defects are associated with severe autoimmune-like manifestations . Although the molecular and biochemical basis of OS have been elucidated, the mechanisms leading to T cell infiltration of peripheral tissues such as skin and gut still remain unsolved. Two murine models with hypomorphic mutations in rag genes reproducing OS features and a murine model of lymphopenia-derived autoimmunity with similar immunopathology were recently described. The aim of this review is to integrate clues on the roles of impaired thymic development and lymphopenia in the pathogenesis of autoimmunity
3D bone biomimetic scaffolds for basic and translational studies with mesenchymal stem cells
No full textMesenchymal stem cells (MSCs) are recognized as an attractive tool owing to their self-renewal and differentiation capacity, and their ability to secrete bioactive molecules and to regulate the behavior of neighboring cells within different tissues. Accumulating evidence demonstrates that cells prefer three-dimensional (3D) to 2D culture conditions, at least because the former are closer to their natural environment. Thus, for in vitro studies and in vivo utilization, great effort is being dedicated to the optimization of MSC 3D culture systems in view of achieving the intended performance. This implies understanding cell–biomaterial interactions and manipulating the physicochemical characteristics of biomimetic scaffolds to elicit a specific cell behavior. In the bone field, biomimetic scaffolds can be used as 3D structures, where MSCs can be seeded, expanded, and then implanted in vivo for bone repair or bioactive molecules release. Actually, the union of MSCs and biomaterial has been greatly improving the field of tissue regeneration. Here, we will provide some examples of recent advances in basic as well as translational research about MSC-seeded scaffold systems. Overall, the proliferation of tools for a range of applications witnesses a fruitful collaboration among different branches of the scientific community
High-rejection birefringent filter for Brillouin mechanical imaging in turbid media
No full textNon-contact Brillouin microscopy holds potential to become an essential tool for mechanobiology, yet this method faces challenges in turbid samples as a consequence of strong Rayleigh scattering. Here, we introduce a common-path birefringence-induced phase delay (BIPD) filter exhibiting an extinction ratio of 65 dB in a single-pass configuration. We demonstrate the capability of the filter to acquire Brillouin maps in turbid samples such as bone tissues of a mouse model of osteopetrosis, a rare genetic disorder with generalized increase in bone density
Generation of 3 clones of induced pluripotent stem cells (iPSCs) from a patient affected by Autosomal Recessive Osteopetrosis due to mutations in TCIRG1 gene
No full textAutosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone density with impairment in bone resorption. Among the genes responsible for ARO, the TCIRG1 gene, coding for the a3 subunit of the osteoclast proton pump, is mutated in more than 50% of the cases, increasing the importance of TCIRG1-iPSCs as disease model. We generated 3 iPSC clones derived from Peripheral Blood Mononuclear Cells (PBMCs) of a patient carrying the heterozygous mutations p.Y512X and c.2236 + 1G > A. A Sendai virus-based vector was used and the iPSCs were characterized for genetic identity to parental cells, genomic integrity, pluripotency, and differentiation ability
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