1,721,044 research outputs found
Bone cells and the mechanisms of bone remodelling
No full text""Bone is a peculiar connective tissue which. functionally interacts with many other organs and tissues,. including bone marrow, lymphoid tissue, kidney, adipose. tissue, endocrine pancreas, brain and gonads. Bone functions. are accomplished by three principal cell types: the osteoblasts,. cells of mesenchymal origin having osteogenic functions, the. osteoclasts, giant multinucleated cells arising from the. monocyte-macrophage line and devoted to resorb bone, and. the osteocytes, the latter arising from mature osteoblasts that,. once deposited the bone matrix, remain trapped in it, becoming. quiescent cells. Osteocytes are known for their role as. mechanosensors, however, old and new evidence showed their. active contribution to mineral homeostasis. Moreover, the. cross-talk between bone cells is crucial, since a correct bone. homeostasis relies on a right coupling between osteoblast and. osteoclast functions. Any deregulation of this coupling is. responsible for bone disease condition, which reflects on other. organs with which bone interacts."
The tight relationship between osteoclasts and the immune system
No full textOsteoimmunology is an interdisciplinary field addressing the interplay between the skeletal and the immune system. A substantial body of evidence demonstrated the existence of two-way regulatory mechanisms that affect both systems, placing them in much closer association to each other than one could ever predict. Inflammatory diseases have long been known to induce alterations in bone metabolism, and inflammatory cytokines play prominent roles in the control of bone resorption, representing communication pathways bridging the two systems. Osteoclasts are particularly linked to the immune cells because they belong to the monocyte/macrophage family, have tight relationships with B and T cells, and differentiate in response to RANKL which is also produced by lymphocytes and regulates lymphopoiesis. Osteoclasts are negatively regulated by cytokines and other factors known for their anti-inflammatory and immune regulatory activity. Finally, they express immune co-receptor typical of immune cells which are indispensable for their differentiation, thus leading to the hypothesis that osteoclasts are immune cells themselves. The underlying principle why an immune cell is required to resorb bone has not yet been elucidated. Data from early literature suggest that the bone matrix could trigger an innate immune response activating giant cells that could destroy large bone areas because of their unique property of resorbing bone extracellularly. Bone resorption could though be prevented by the physical barrier made by osteoblasts and lining cells, whose retraction would be required to give access to osteoclasts when specific pathways signal their precursors to differentiate and mature osteoclasts to reach the uncovered bone surface
Osteoclast genetic diseases
No full textBone is a specialized connective tissue that performs many important functions: (i)mechanical, supporting the whole body and allowing the movements; (ii) protective, shielding many vital organs, such as brain, lung, heart and bone marrow; (iii) metabolic, regulating the homeostasis of calcium and phosphate; (iv) endocrine,
regulating kidney function and
contributing to global energy balance and male fertility. Bone is a dynamic tissue, subjected to a continuous
process of renewal and remodelling in which bone resorption by osteoclasts and bone formation by osteoblasts occur at the same site along the bone surface. About 10% of bone is replaced each year, with complete skeletal renewal every 10 years. An
imbalance between osteoblast and osteoclast activities can cause serious consequences: if
bone formation is enhanced or bone resorption is impaired, bone mass is increased, and vice versa. Often osteoclast diseases are monogenic, and in
many of them the responsible gene and the respective function have been identified, while for other osteoclast diseases the causative gene has not been isolated or the exact function of the matching protein still remains unknown. In this review, a brief description of osteoclast biology will be provided and examples of genetic osteoclast diseases, including osteopetrosis, pycnodysostosis and Paget’s disease of bone, will be discussed
New Experimental Therapeutic Approach by siRNA for Autosomal Dominant Osteopetrosis (ADO)
No full textOsteoclast receptors and signaling
No full textOsteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Besides the well known Receptor Activator of Nuclear factor-kappa B (RANK), RANK ligand and osteoprotegerin axis, a variety of factors tightly regulate osteoclast formation, adhesion, polarization, motility, resorbing activity and life span, maintaining bone resorption within physiological ranges. Receptor-mediated osteoclast regulation is rather complex. Nuclear receptors, cell surface receptors, integrin receptors and cell death receptors work together to control osteoclast activity and prevent both reduced or increased bone resorption. Here we will discuss the signal transduction pathways activated by the main osteoclast receptors, integrating their function and mechanisms of action. (C) 2008 Elsevier Inc. All rights reserved
Genetics, pathogenesis and complications of osteopetrosis
No full textHuman osteopetrosis is a rare genetic disorder caused by osteoclast failure, which ranges widely in severity. In the most severe forms, deficient bone resorption prevents enlargement of bone cavities, impairing development of bone marrow, leading to hematological failure. Closure of bone foramina causes cranial nerve compression with visual and hearing deterioration. Patients also present with osteosclerosis, short stature, malformations and brittle bones. This form is fatal in infancy, has an autosomal recessive inheritance and is cured with hematopoietic stem cell transplantation, with a rate of success 50% of cases, the ClCN7 and the OSTM1 genes, which have closely related function and account for approximately 10% of cases, also presenting with neurodegeneration. Further genes are implicated in rare forms with various severities and association with other syndromes and, recently, the RANKL gene has been found to be mutated in a subset of patients lacking osteoclasts. Autosomal recessive osteopetrosis may also have intermediate severity, with a small number of cases due to loss-of-function mutations of the CAI1 or the PLEKHM1 genes. Dominant negative mutations of the ClCN7 gene cause the so-called Albers-Schonberg disease, which represents the most frequent and heterogeneous form of osteopetrosis, ranging from asymptomatic to intermediate/severe, thus suggesting additional genetic/environmental determinants affecting penetrance. Importantly, recent work has demonstrated that osteoblasts may also contribute to the pathogenesis of the disease, either because they are affected by intrinsic defects, or because their activity may be enhanced by deregulated osteoclasts abundantly present in most forms. Therapy is presently unsatisfactory and effort is necessary to unravel the gene defects yet unrecognized and identify new treatments to improve symptoms and save life. (C) 2007 Elsevier Inc. All rights reserved
Bone control of muscle function
Full text linkBone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Muscle influence on bone has been deeply studied, and recent studies identified irisin as new molecule involved in this crosstalk. Muscle regulation by bone needs to be extensively investigated since in the last few years osteocalcin was recognized as a key molecule in the bone–muscle interaction. Osteocalcin can exist in two forms with different degrees of carboxylation. The undercarboxylated form of osteocalcin is a hormone released by the bone matrix during the osteoclast bone resorption and can bind its G-protein coupled receptor GPRC6A expressed in the muscle, thus regulating its function. Recently, this hormone was described as an antiaging molecule for its ability to regulate bone, muscle and cognitive functions. Indeed, the features of this bone-related hormone were used to test a new therapeutic approach for sarcopenia, since injection of osteocalcin in older mice induces the acquirement of physical abilities of younger animals. Even if this approach should be tested in humans, osteocalcin represents the most surprising molecule in endocrine regulation by the skeleton
Recent advances in mesenchymal stem cell immunomodulation. The role of microvesicles
No full textMesenchymal stem cells are the most widely used cell phenotype for therapeutic applications, the main reasons being their well-established abilities to promote regeneration of injured tissues and to modulate immune responses. Efficacy was reported in the treatment of several animal models of inflammatory and autoimmune diseases and, in clinical settings, for the management of disorders such as GVHD, Systemic Lupus Erythematosus, multiple sclerosis and inflammatory bowel disease. The effects of mesenchymal stem cells are believed to be largely mediated by paracrine signals, and several secreted molecules have been identified as contributors to the net biological effect. Recently, it has been recognized that bioactive molecules can be shuttled from cell to cell packed in microvesicles, tiny portions of cytoplasm surrounded by a membrane. Coding and non-coding RNAs are also carried in such microvesicles, transferring relevant biological activity to target cells. Several reports indicate that the regenerative effect of mesenchymal stem cells can be reproduced by microvesicles isolated from their culture medium. More recent evidence suggests that the immunomodulatory effects of mesenchymal stem cells are also at least partially mediated by secreted microvesicles. These findings allow better understanding of the mechanisms involved in cell-to-cell interaction and may have interesting implications for the development of novel therapeutic tools in place of the parent cells
Lipocalin 2 is a novel mechanoresponding gene involved in osteoblast differentiation and osteoblast-osteoclast cross-talk
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