Although high inorganic phosphate (Pi) concentration in culture media directly inhibits generation of new osteoclasts and also inhibits bone resorption by mature osteoclasts, its precise mechanism and the physiological role have not been elucidated. The present study was performed to investigate these issues. Increase in extracellular Pi concentration ([Pi](e)) (2.5-4 ...

As the TNF and TNFR superfamilies have grown to more than two dozen combined members over the past 30 years, their involvement in interactions between immune cells, with regard to the events governing cellular differentiation, activation, and survival have been well established. The recently identified TNF superfamily cytokine, TRANCE (RANKL/OPGL/ODF/TNFSF11), ...

Triggering receptors expressed by myeloid cells (TREMs) belong to a rapidly expanding family of receptors that include activating and inhibitory isoforms encoded by a gene cluster linked to the MHC. TREM1 and TREM2 activate myeloid cells by signalling through the adaptor protein DAP12. TREM1 triggers phagocyte secretion of pro-inflammatory chemokines ...

It has been proposed - but remains controversial - that estrogen's effects on various tissues may be mediated by different cell signaling pathways. Researchers have identified a synthetic ligand that activates only a subset of these pathways, suggesting that bypass of the traditional estrogen pathway can prevent bone loss without ...

Bone resorption is responsible for the morbidity associated with a number of inflammatory diseases such as rheumatoid arthritis, orthopedic implant osteolysis, periodontitis and aural cholesteatoma. Previous studies have established nitric oxide (NO) as a potentially important mediator of bone resorption. NO is a unique intercellular and intracellular signaling molecule involved ...

Pigment dispersion syndrome causes iris pigment release and often progresses to elevated intraocular pressure and pigmentary glaucoma (PG). Because melanin pigment can have adjuvant like properties and because the Gpnmb gene, which contributes to pigment dispersion in DBA/2J (D2) mice, is expressed in dendritic cells, we tested the hypothesis that ...

During the past decade, we have increased greatly our understanding of the pathogenesis of postmenopausal osteoporosis, a major cause of morbidity and mortality. We know now that estrogen regulates the expression of cytokines that target cell types involved in modulating bone turnover. Although early work demonstrated that tumor necrosis factor ...

The hallmark of myelodysplastic syndrome (MDS) is enhanced apoptosis in myeloid, erythroid, and megakaryocytic cells in the bone marrow leading to ineffective hematopoiesis. Recent studies suggested that immunological and microenvironmental factors play a role in the pathophysiology of this disease. We report a significant increase in apoptosis in bone marrow ...

Parathyroid hormone (PTH) has biphasic effects on bone: continuous treatment is catabolic whereas intermittent treatment is anabolic. The mechanism(s) responsible for these differing effects are still unclear, partly because of the previous non-availability of a model system in which effects on both formation and resorption indices could be studied concomitantly. ...

Myelodysplastic syndromes (MDS) are neoplastic dyscrasias characterized by peripheral cytopenia, despite a normocellular or hypercellular bone marrow. In the past decade, it has become apparent that this ineffective hemopoiesis is largely caused by excessive apoptosis of myeloid precursors. There is no evidence for gain-of-function mutations within the apoptotic machinery in ...

Proinflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFalpha), have been implicated in the dysregulation of bone and cartilage remodelling characteristic of rheumatoid arthritis (RA). With respect to bone remodelling, both of these cytokines have been shown to up-regulate the production of the receptor activator of nuclear ...

Doxorubicin induces apoptosis in a variety of cells. We investigated the expression and function of various tumor necrosis factor (TNF)alpha-homologues and their receptors. CEM cells did not differentially express any one of the TNFalpha-homologous receptors investigated nor TNF-related apoptosis-inducing ligand or TNF-related weakly apoptosis-inducing ligand (TWEAK) in the presence of ...

Nitric oxide has been shown to play an important role in regulation of bone resorption. However, the role of endogenous nitric oxide on osteoclast activity remains still controversial. In this work, using RT-PCR amplification, we demonstrated that rabbit mature osteoclasts express mRNA encoding for neuronal nitric oxide synthase suggesting that ...

Lipopolysaccharide is a pathogen that causes inflammatory bone loss. Monocytes and macrophages produce proinflammatory cytokines such as IL-1, TNF-alpha, and IL-6 in response to LPS. We examined the effects of LPS on the function of osteoclasts formed in vitro in comparison with its effect on bone marrow macrophages, osteoclast precursors. ...

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are candidate cytokines which are produced by osteoblastic linage cells and promote osteoblast apoptosis, osteoclastogenesis and bone resorption. Here, we examined the effect of (+)-catechin, one of the most common grape flavonols, on osteoblastic MC3T3-E1 cells. (+)-Catechin caused a significant elevation of cell ...

Sintered dicalcium pyrophosphate (SDCP), a synthetic compound, has proved to be both bioabsorbable and biocompatible in vivo. Recent work in our institute also has demonstrated that the ingestion of SDCP can increase bone mass in the ovariectomized rat. In this study, we used an in vitro cell culture model to ...

Bacterially induced bone infections often result in significant local inflammatory responses which are coupled with loss of bone. However, the mechanisms necessary for the protective host response, or those responsible for pathogen-induced bone loss, are not clear. Recent evidence demonstrates that bacterially infected osteoblasts secrete chemokines and cytokines, suggesting that ...

Leptin has been advocated as a centrally acting factor responsible for inhibiting accumulation of bone mass. However, recent investigations unequivocally establish leptin as a local (autocrine) factor expressed by osteoblasts. Exogenously added leptin causes osteoblastic cell proliferation and differentiation, while also rendering osteoblasts more efficacious in terms of mineralization. Leptin ...

BACKGROUND: Severe bone destruction due to inappropriate osteoclastogenesis is a prominent feature of multiple myeloma (MM). MM increases bone loss by disrupting the checks that normally control signaling by receptor activator of nuclear factor kappaB ligand (RANK-L, also called TRANCE [tumor necrosis factor-related, activation-induced cytokine], osteoprotegerin ligand [OPG-L], osteoclast differentiation ...

Bone cell apoptosis is seen at sites of active turnover. We hypothesize that at these sites, factors released from resorbing bone induce apoptosis of vicinal cells. Related to this observation, earlier studies indicate that an elevation in the level of inorganic phosphate ions combined with a modest increase in the ...

PURPOSE: TNFalpha and IL-1alpha are proinflammatory cytokines that are abundant in periprosthetic tissues. These cytokines stimulate bone resorption and have recently been shown to directly induce osteoclast formation in mouse marrow cultures. We examined whether TNFalpha and IL-1alpha can directly induce osteoclast formation from human arthroplasty-derived (CD14(+)) macrophages by a ...

Studies on the effect of estrogens (E(2)) on the expression of vitamin D receptor (VDR) and its bioresponse in bone have demonstrated that E(2) modulate activity and increase the number of VDRs in vitro; however, no in vivo studies have been pursued to assess this interaction. Our study identifies the ...

Aseptic loosening and osteolysis are considered the main long-term problems of hip arthroplasty. Pathogenesis of periprosthetic osteolysis is multifactorial, and both the biological and mechanical factors seem to play an important role. Bearing surfaces continuously generate excessive amounts of micron and submicron particles provoking an adverse inflammatory response of periprosthetic ...

Spondyloarthropathies (SpA) share clinical features such as sacroiliitis, axial immobility, and peripheral arthropathies. They also share a strong association with human leukocyte antigen-B27, implicating T cells and antigen-presenting cells in the disease process. Inflammation seems to underlie the pathogenesis of SpA, particularly in the axial skeleton and entheses. Pathologic bone ...

There is compelling evidence that the most important factor in late periprosthetic bone resorption is an inflammatory reaction to debris. Based on results from several laboratories, it seems likely that opsonized particles activate the macrophage nuclear factor-kappa B signal transduction system via membrane receptors, leading to release of tumor necrosis ...

Macrophage colony-stimulating factor (M-CSF) is known as one of the factors essential for osteoclast development. In the present study, we examined effects of M-CSF on the apoptotic pathway of osteoclast precursors and their underlying molecular mechanisms. Osteoclast precursors underwent apoptosis in the absence of M-CSF, even in the presence of ...

Genetically modified mice and cells have provided important insights into the biological functions of the dimeric transcription factor complex AP1, in particular into its role in skeletal development. Data obtained from knockout mice revealed that some components, such as c-Fos are key regulators of bone cell differentiation, whereas others, like ...

Anti-resorptive bisphosphonates, such as pamidronate, are an effective treatment for osteolytic disease and hypercalcaemia in patients with multiple myeloma, but have also been shown to cause apoptosis of myeloma cell lines in vitro. In this study, we found that a single infusion of pamidronate, in 16 newly diagnosed patients with ...

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed, which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal ...

TNFalpha and IL-1alpha are potent stimulators of bone resorption in vivo and in vitro. Recently, it has been demonstrated that these two cytokines directly induce osteoclastogenesis in mouse marrow cultures. This study determined whether TNFalpha (+/- IL-1alpha) is also capable of inducing human osteoclastogenesis. The CD14(+) monocyte fraction of human ...

A growing body of evidence has shown that bacterially challenged bone-forming osteoblasts are a significant source of an array of cytokines and chemokines that can support immune responses during bone disease. In the present study, Staphylococcus aureus and Salmonella, two common pathogens of bone, were investigated for their ability to ...

BACKGROUND: Pathological bone resorption (marginal erosions and juxta-articular osteoporosis) by osteoclasts commonly occurs in rheumatoid arthritis (RA). OBJECTIVES: To define the nature of the mononuclear precursor cells from which osteoclasts are formed in inflamed synovial tissues and to determine the cellular and humoral factors which influence osteoclast differentiation. METHOD: Macrophage ...

A report of the meeting "Third International Conference on Osteopontin and Related Proteins", San Antonio, TX, USA, 10 to 12 May 2002. At a recent meeting, the structure and biology of the cytokine osteopontin were discussed. The molecule is essential for cellular immune responses and for the remodeling of cardiovasculature ...

Osteoclasts, the cells capable of resorbing bone, are derived from hemopoietic precursor cells of monocyte-macrophage lineage. The same precursor cells can also give rise to macrophages and dendritic cells, which are essential for proper immune responses to various pathogens. Immune responses to microbial pathogens are often triggered because various microbial ...

Thalidomide (Thal) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thal formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth ...

From the early 1900s, it has been known that ionizing radiation (IR) impairs hematopoiesis through a variety of mechanisms. IR exposure directly damages hematopoietic stem cells and alters the capacity of bone marrow stromal elements to support and/or maintain hematopoiesis in vivo and in vitro. Exposure to IR induces dose-dependent ...

Bone is regulated by evolutionarily conserved signals that balance continuous differentiation of bone matrix-producing cells against apoptosis and matrix removal. This is continued from embryogenesis, where the skeleton differentiates as a solid mass and is shaped into separate bones by cell death and proteolysis. The two major tissues of the ...

Bacteria or their products may cause chronic inflammation and subsequent bone loss. This inflammation and bone loss may be associated with significant morbidity in chronic otitis media, periodontitis, endodontic lesions, and loosening of orthopedic implants caused by lipopolysaccharide (LPS)-contaminated implant particles. Currently, it is not clear how bacteria or endotoxin-induced ...

OBJECTIVE: To evaluate the potential of viral interleukin-10 (vIL-10) gene therapy as an approach to prevent wear debris-induced inflammation, osteoclastogenesis, and bone resorption as it relates to periprosthetic osteolysis in patients with total joint replacements. METHODS: Replication-defective adenovirus vectors expressing vIL-10 (AdvIL-10) or LacZ (AdLacZ) target genes were used to ...

Recent studies have shown that stimulation of osteoclastogenesis in cocultures of osteoblasts and spleen cells in response to prostaglandin E2 (PGE2) is markedly decreased when the osteoblasts are derived from cells lacking either the EP2 or the EP4 receptor. Induction of osteoclast formation requires upregulation of receptor activator of nuclear ...

Bacterial infection results in inflammatory responses that may lead to soft-tissue damage and bone resorption. However, the mechanisms by which different bacteria contribute to lesions of endodontic origin are not fully understood. This study examined the response to Streptococcus mutans and Porphyromonas endodontalis in two cell types that are involved ...

RANK, RANKL, and OPG have well established regulatory effects on bone metabolism. RANK is expressed at very high levels on osteoclastic precursors and on mature osteoclasts, and is required for differentiation and activation of the osteoclast. The ligand, RANKL binds to its receptor RANK to induce bone resorption. RANKL is ...

Glucocorticoids depress bone formation by inhibiting osteoblastogenesis and increasing osteoblast apoptosis. However, the role of bone resorption in the initial rapid phase of bone loss characteristic of glucocorticoid-induced osteoporosis is unexplained, and the reason for the efficacy of bisphosphonates in this condition remains unknown. We report that in murine osteoclast ...

Angiogenesis and immune suppression are the two important factors responsible for embryo implantation and development of tumor. Therefore, disruption of angiogenesis and upliftment of immune function is essential for control of tumor growth as well as to regulate the activity of post coital contraceptives. BIM is an immunomodulatory cytokine obtained ...

Peroxynitrite (PN), a nitric oxide (NO*)-derived anion, has been associated with NO* damage in various cell types. We examined the effects of adding PN to cultured human osteoblast-like (hOB) cells obtained after hip arthroplasty. Exposure to PN (0.1-0.4 mM) decreased both hOB proliferation and differentiation, measured by [3H]thymidine uptake and ...

Osteoinductive molecules are characterized by their ability to promote the formation of bone. Most osteoinductive molecules are cytokines, which are extracellular proteins or peptides that mediate cell to cell signaling. Examples of osteoinductive cytokines are certain bone morphogenetic proteins and some growth and differentiation factors. Some osteoinductive molecules are not ...

Osteoclasts and osteoblasts are responsible for strict bone maintenance with a balance between bone formation and resorption by interacting with each other. Recently, it has been revealed that osteoblasts/stromal cells regulate differentiation of osteoclasts/hematopoietic cells by two factors, the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) on the plasma ...

Chondrocytes contained within the epiphyseal growth plate promote rapid bone growth. To achieve growth, cells activate a maturation program that results in an increase in chondrocyte number and volume and elaboration of a mineralized matrix; subsequently, the matrix is resorbed and the terminally differentiated cells are deleted from the bone. ...

The presence of cholesterol crystals, macrophages, and foreign giant cells has been associated with impaired bone healing of periapical lesions. Therefore, we investigated whether macrophages exposed to cholesterol crystals can release factors changing the activity of bone-resorbing osteoclasts. Mouse peritoneal macrophages treated with cholesterol crystals in vitro produced factor(s) that ...

Bone-resorbing osteoclasts are formed from hemopoietic cells of the monocyte-macrophage lineage under the control of bone-forming osteoblasts. We have cloned an osteoblast-derived factor essential for osteoclastogenesis, the receptor activator of NF-kappaB ligand (RANKL). Synovial fibroblasts and activated T lymphocytes from patients with rheumatoid arthritis also express RANKL, which appears to ...