Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease.

Macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion.

Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats.

Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats.

NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy.

The proinflammatory and catabolic cytokine IL-1β has been implicated in the pathogenesis of osteoarthritis (OA) by mediating synovial inflammation and cartilage degeneration. Although synovial macrophages are suggested to be the source of IL-1β, the mechanism remains unclear. Ectopic deposition of hydroxyapatite (HA) crystals in joints is closely associated with OA and other arthropathies, but the precise role of HA in arthritis pathogenesis has not been clearly demonstrated.

Important roles of PI3Kgamma in osteoclastogenesis and bone homeostasis.

G protein-coupled receptor-regulated PI3Kgamma is abundantly expressed in myeloid cells and has been implicated as a promising drug target to treat various inflammatory diseases. However, its role in bone homeostasis has not been investigated, despite the fact that osteoclasts are derived from myeloid lineage. We therefore carried out thorough bone phenotypic characterization of a PI3Kgamma-deficient mouse line and found that PI3Kgamma-deficient mice had high bone mass.

Dramatic increase in cortical thickness induced by femoral marrow ablation followed by a 3-month treatment with PTH in rats.

We previously reported that following mechanical ablation of the marrow from the midshaft of rat femurs, there is a rapid and abundant but transient growth of bone, and this growth is enhanced and maintained over a 3-week period by the bone anabolic hormone parathyroid hormone (PTH). Here, we asked whether further treatment with PTH or bisphosphonates can extend the half-life of the new bone formed in lieu of marrow. We subjected the left femur of rats to mechanical marrow ablation and treated the animals 5 days a week with PTH for 3 weeks (or with vehicle as a control) to replace the marrow by bone.

Role of MKP-1 in osteoclasts and bone homeostasis.

Bone mass is maintained through the complementary activities of osteoblasts and osteoclasts; yet differentiation of either osteoblasts and osteoclasts engages the mitogen-activated protein kinase (MAPK) pathway. The MAPKs are negatively regulated by a family of dual-specificity phosphatases known as the MAPK phosphatases (MKPs). MKP-1 is a stress-responsive MKP that inactivates the MAPKs and plays a central role in macrophages; however, whether MKP-1 plays a role in the maintenance of bone mass has yet to be investigated.

Deletion of mitogen-activated protein kinase phosphatase 1 modifies the response to mechanical bone marrow ablation in a mouse model.

The maintenance of bone mass results from a delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts. Understanding these processes is essential for the development of effective treatments for skeletal diseases. Mechanical bone marrow ablation provides a unique animal model to study bone repair and the roles of specific genes in this process.

Methods to fuse macrophages in vitro.

Macrophages are mononucleate cells that fuse in rare and specific instances to form osteoclasts in bone or giant cells in chronic inflammatory conditions. Because of the central role these cells play in bone metabolism and in inflammation, respectively, methods to study their formation in vitro are described.

Macrophage fusion: molecular mechanisms.

Macrophages are the most versatile, plastic, and mobile cells in the animal kingdom. They are present in all tissues and might even define a true " body-wide" network that maintains health and ensures the repair of tissues and organs. In specific and rare instances, macrophages fuse to form multinucleate osteoclasts and giant cells in bone and in chronic inflammatory reactions, respectively.

Replacement of bone marrow by bone in rat femurs: the bone bioreactor.

During development and repair of bone, two distinct yet complementary mechanisms, intramembranous and endochondral, mediate new bone formation via osteoblasts. Because mechanical bone marrow ablation leads to the rapid and transient formation of new bone in the marrow cavity, we postulated that parathyroid hormone (PTH), which is a bone anabolic hormone, enhances the formation of new bone that forms after marrow ablation. We subjected the left femur of rats to mechanical marrow ablation, or sham operation, and injected the animals daily with PTH or vehicle for 1, 2, or 3 weeks in a first experiment, then with PTH, parathyroid hormone-related peptide (PTHrP), or vehicle for 3 weeks in a second experiment.

CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts.

Fusion of macrophages is an essential step in the differentiation of osteoclasts, which play a central role in the development and remodeling of bone. Osteoclasts are important mediators of bone loss, which leads, for example, to osteoporosis. Macrophage fusion receptor/signal regulatory protein alpha (MFR/SIRPalpha) and its ligand CD47, which are members of the Ig superfamily (IgSF), have been implicated in the fusion of macrophages.

Cell-cell fusion.

Cell-cell fusion is a highly regulated and dramatic cellular event that is required for development and homeostasis. Fusion may also play a role in the development of cancer and in tissue repair by stem cells. While virus-cell fusion and the fusion of intracellular membranes have been the subject of intense investigation during the past decade, cell-cell fusion remains poorly understood.

[Macrophage fusion: are somatic and cancer cells possible partners?].

The fusion of cells is a fundamental biological event that plays a central role in a variety of developmental and homeostatic processes. Macrophages are present in all tissues and can initiate interaction and fusion. The putative macrophage-fusion machinery is still poorly understood, but some of its components have been identified.

The intracellular domain of CD44 promotes the fusion of macrophages.

Macrophages seed all tissues in which they have the ability, in specific and rare instances, to fuse with themselves and to differentiate into osteoclasts in bone or into giant cells in chronic inflammatory reactions. Although these cells play a central role in osteoporosis and in foreign body rejection, respectively, the molecular mechanism used by macrophages to fuse remains poorly understood. Macrophages might also fuse with somatic and tumor cells to promote tissue repair and metastasis, respectively.

Macrophage fusion: the making of osteoclasts and giant cells.

The fusion of cells is a fundamental biological event that is essential for a variety of developmental and homeostatic processes. Fusion is required for the formation of multinucleated osteoclasts and giant cells, although the mechanisms that govern these processes are poorly understood. A new study now reveals an unexpected role for the receptor, dendritic cell-specific transmembrane protein (DC-STAMP), in this process.

Macrophage fusion: are somatic and cancer cells possible partners?

Macrophages are present in all tissues and can fuse with themselves to differentiate into multinucleate osteoclasts or giant cells that play a central role in osteoporosis and chronic inflammatory diseases, respectively. Yet, the mechanism by which they fuse remains uncharacterized. The macrophage fusion receptor (MFR) and its ligand CD47 might mediate homotypic fusion of macrophages and allow for their recognition as 'self' before fusion.

IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation.

Osteoporosis is a serious problem worldwide; it is characterized by bone fractures in response to relatively mild trauma. Osteoclasts originate from the fusion of macrophages and they play a central role in bone development and remodeling via the resorption of bone. Therefore, osteoclasts are important mediators of bone loss that leads, for example, to osteoporosis.

Histamine participates in the early phase of trabecular bone loss in ovariectomized rats.

We have previously reported that cimetidine, a reference H2 receptor antagonist, attenuates the initial osteoclastic burst and subsequent trabecular bone loss induced by ovariectomy (ovx) in rats. This study was designed to determine whether these effects are specific to H2 antagonism. To this end, we compared the effects of two H2 receptor antagonists, cimetidine and famotidine.

Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis).

Strontium ranelate (S12911) has previously been shown to stimulate bone formation and inhibit bone resorption in rats. To determine whether strontium ranelate affects normal bone remodeling, we studied the effect of strontium ranelate on alveolar bone in monkeys. Strontium ranelate, at dosages of 100, 275, and 750 mg/kg per day, or vehicle, were given by gavage to 31 normal adult monkeys (Macaca fascicularis) (15 males, 16 females), aged 3-4 years.

Osteoclasts and giant cells: macrophage-macrophage fusion mechanism.

Membrane fusion is a ubiquitous event that occurs in a wide range of biological processes. While intracellular membrane fusion mediating organelle trafficking is well understood, much less is known about cell-cell fusion mediating sperm cell-oocyte, myoblast-myoblast and macrophage-macrophage fusion. In the case of mononuclear phagocytes, their fusion is not only associated with the differentiation of osteoclasts, cells which play a key role in the pathogenesis of osteoporosis, but also of giant cells that are present in chronic inflammatory reactions and in tumours.

CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation.

The macrophage fusion receptor (MFR), also called P84/BIT/SIRPalpha/SHPS-1, is a transmembrane glycoprotein that belongs to the superfamily of immunoglobulins. Previously, we showed that MFR expression is highly induced at the onset of fusion in macrophages, and that MFR appears to play a role in macrophage-macrophage adhesion/fusion leading to multinucleation. The recent finding that IAP/CD47 acts as a ligand for MFR led us to hypothesize that it interacts with CD47 at the onset of cell-cell fusion.

Inhibition of NF-kappaB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide.

Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by the central and peripheral nervous systems and by endocrine cells. CGRP exerts diverse biological effects on the cardiovascular, gastrointestinal, respiratory, central nervous and immune systems. Little is known, however, about the molecular mechanisms that mediate CGRP effects.

Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice.

The neuropeptide calcitonin gene-related peptide (CGRP) is concentrated in fine sensory nerve endings innervating all tissues, including bone. CGRP inhibits osteoclasts, stimulates insulin-like growth factor I and inhibits tumor necrosis factor alpha production by osteoblasts in vitro. To investigate the role of CGRP in bone in vivo, mice were engineered to express CGRP in osteoblasts by placing the human CGRP gene under the control of the rat osteocalcin promoter (Ost-CGRP tg+ mice).

CD44 occupancy prevents macrophage multinucleation.

Cells of the mononuclear phagocyte lineage have the capability to adhere to and fuse with each other and to differentiate into osteoclasts and giant cells. To investigate the macrophage adhesion/fusion mechanism, we focused our attention on CD44, a surface glycoprotein known to play a role in hematopoietic cell-cell adhesion. We report that CD44 expression by macrophages is highly and transiently induced by fusogenic conditions both in vitro and in vivo.