Bone Abstracts

Multiple myeloma (MM)-bone disease occurs in 70 to 80% of patients at MM diagnosis, and up to 90% at relapse; skeletal related events cause high morbidity and mortality. MM-bone disease consists of lytic lesions arising as a consequence of an unbalanced bone remodelling due to osteoclast (OC) activation, and osteoblast inactivation. Osteoclastogenesis may be under immune cell regulation through the production of numerous cytokines, such as LIGHT/TNFSF14, a newly identified mem...

Bisphosphonates (BPs) are used to treat bone diseases characterized by excessive bone resorption. However, BPs can negatively affect the jaw bone by causing osteonecrosis of the jaw. Previously, we showed that BPs differently affect long-bone and jaw osteoclast precursors. Administration of BPs in vivo reduced the number of jaw bone marrow cells, without affecting long-bone marrow cells. Yet, BPs increased bone volume and mineral density of both long bone and jaw. Her...

Mutations in PLEKHM1 cause bone disease in humans and animals. Truncations causedeficient bone resorption by osteoclasts leading to osteopetrosis. A gain-of-function point mutation causes increased resorption leading to osteopenia. We and others have shown that PLEKHM1, a multi-modular protein, interacts with the small GTPase rab7 and is involved in vesicle trafficking, secretion, and membrane biogenesis. To investigate other interactions of PLEKHM1 we performed tandem affinit...

Lipid raft microdomains have important role in cellular signaling. Caveolae are a specialized type of lipid rafts that are stabilized by oligomers of caveolin protein. Here we showed that caveolin-1 (Cav-1) is a critical membrane structural protein of osteoclast. In microarray analysis, we found that caveolin-1 was significantly up-regulated by RANKL. Knock-down of Cav-1 in bone marrow derived-macrophage reduced osteoclastogenesis. Consistent with the in vitro results...

Interleukin-34 (IL-34) is a newly discovered cytokine which regulates, like macrophage-colony stimulating factor (M-CSF), the differentiation/activation of the myeloid lineage. IL-34 and M-CSF are homodimers known to bind to the M-CSF receptor (M-CSFR) in a competitive manner. In this system, IL-34 can substitute for the M-CSF to induce osteoclastic differentiation. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the...

CCN family member 2(CCN2)/Connective tissue growth factor (CTGF) is a multi-functional factor in proliferation, differentiation and migration of mesenchymal cells such as chondrocytes, osteoblasts and vascular endothelial cells. Recently, we also reported that CCN2/CTGF promotes osteoclastgenesis via induction of and interaction with DC-STAMP. We and other researchers reported that CCN2 binds to cytokines and receptors and modified their signaling. Therefore, we compr...

The interaction of Receptor Activator of NFkB ligand (RANKL) with its cognate receptor RANK is crucial for osteoclast formation. We studied eight point mutations within human RANK associated with rare forms of osteopetrosis to gain mechanistic insights into the regulation of RANK signalling.We investigated the role of the oligomerisation domain within the cytoplasmic region of RANK studying two mutations (W434X and G280X) identified in rare cases of oste...

The mature human skeleton is a metabolically active organ that is continuously resorbed and rebuilt by osteoclasts and osteoblasts. Dietary supplementation of selected long chain polyunsaturated fatty acids (LCPUFAs) has shown effects on bone turnover. Most research on LCPUFAs has been done using commercially available cell lines and further clarification of the cellular effects on models relevant to humans is required. After ethical approval, peripheral blood was collected fr...

The receptor activator of NF-kB (RANK) and ITAM-containing adaptors have been identified as essential factors involved in osteoclast formation and bone remodeling, but their mechanisms and interacting factors have not yet been fully identified. Here we report that early estrogen-induced gene 1 (EEIG1), a novel RANK ligand (RANKL)-inducible protein, physically interacts with RANK and further associates with Gab2, PLCg2, and Tec/Btk kinases by RANKL stimulation. Overexpression o...

Osteoclasts secrete acid and cathepsin K to dissolve the mineral and digest the organic matrix of bone, cartilage and dentine. The secretions are by necessity destructive and potentially harmful to the cell itself and are therefore trafficked through the cell in membrane bound vesicles. Secretion takes place over a specialised membrane compartment, the ruffled border, which is only present in resorbing osteoclasts. The ruffled border membrane and the vesicles in its vicinity h...

Aims: To investigate the role of interleukin-6 (IL-6) as a modulator of osteoclastic resorption in vitro in acute Charcot osteoarthropathy.Material and methods: Peripheral blood mononuclear cells were isolated from six patients with acute Charcot osteoarthropathy, five diabetic and five healthy controls and cultured in vitro on bovine bone disks for 21 days in the presence of i) macrophage-colony stimulating factor (M-CSF) and receptor ...

This study examined the anti-osteoclastogenic effect of n-butanol extracts of Panax notoginseng on the receptor activator of NF-kB ligand (RANKL) induced RAW264.7 cells. Panax notoginseng is commonly used to treat chronic liver disease. Notoginseng has many beneficial effects, such as the suppression of liver fibrosis and anti-cancer activities. Notoginseng contains several biologically active components, such as ginsenosides Rb1, Rg1...

RANKL, the receptor activator of nuclear factor kappa B ligand, is an essential factor for the formation of mature osteoclasts. Together with its receptor RANK and its antagonist Osteoprotegerin (OPG) RANKL is a key regulator in bone metabolism1. RANKL is a membrane-bound protein that can be segregated to a soluble form (sRANKL), whereas only the latter has been reported to be bioactive2. Due to its low circulating levels and the nature of the analyte bin...

Background: Osteoclasts are unique multinucleated cells that originate from the fusion of monocytes. They are the only cells known to be capable of bone resorption. Interestingly, the foreign body multinucleated giant cell (FBGC) arises from the same lineage as the osteoclast, and they share numerous similar characteristics, among which the expression of tartrate resistant acid phosphatase (TRAcP). Yet, it is not known whether the FBGC has the capacity to resorb bone.<p cl...

Gaucher’s disease is a glycolipid storage disorder caused by an autosomally inherited deficiency of the lysosomal enzyme glucocerebrosidase. The majority of patients with Gaucher’s disease develop abnormal bone remodelling with severe consequences, including osteonecrosis, bone crises, and osteoporosis related fractures. Although enzyme replacement therapy is effective at reversing many of the pathological consequences, and preventing further progression of this dise...

Chronic tophaceous gout is the natural evolution of untreated gouty arthritis and is characterized by the deposition of solid monosodium urate crystal aggregated in a variety of tissue including joints, bursae and tendons. Tophaceous gout is well-known to cause bone erosions and is characterized by enhanced osteoclasts development. Peripheral blood mononuclear cells (PBMCs) from patients with severe erosive gout showed the preferential ability to transform into osteoclast-like...

Inflammatory processes play a role in osteoclastogenesis. C-reactive protein (CRP), an acute phase reactant that reflects different degree of inflammation. More recently, accumulating evidence suggest that CRP is not only an inflammatory marker but also direct cause of diseases. Therefore, we examined the direct effects of CRP on osteoclast formation using RAW 264.7 cells. CRP significantly inhibited RANKL-induced TRAP-positive multinucleated cell formation in RAW 264.7 cell c...

Bone remodeling and maintenance require a fine balance between bone formation of osteoblasts and resorption of osteoclasts. Therefore, various skeletal disorders cause by imbalanced differentiation and activities of these cells. RANKL (receptor activator of NF-kB ligand) induces Ca2+ oscillations and activates NFATc1 (nuclear factor of activated T cells i) during osteoclast differentiation. Although Ca2+ oscillations play a key role for osteoclastogenesis...

Tyrosine kinase c-Src plays an important role in actin ring formation and bone resorption activity in osteoclasts. Therefore, c-Src has been targeted for the treatment of osteolytic disorders. In the present study, we investigated anti-resorptive effect of dibenzazepine (DBZ), one of the γ-secretase inhibitors (GSIs), on osteoclast-mediated excessive bone resorption. DBZ did not affect osteoclast differentiation, but disturbed actin ring formation and inhibited osteoclast...

The P2Y14 (purinergic receptor P2Y, G protein coupled, 14) receptor for UDP-glucose and other UDP-sugars has been implicated in the regulation of the stem cell compartment as well as neuroimmune function. However, the role of P2Y14 in osteoclast formation is completely unknown. We found that RANKL selectively induced P2Y14 among seven mammalian P2Y receptors when analysed at both the mRNA and protein level, but inhibitors of the MAP pathway suppressed induction of P2Y14 protei...

Receptor activator of nuclear factor kappa B ligand (RANKL)-induced activation of NF-κB and MAPKs signaling pathways is critical to osteoclastogenesis. Glossogyne tenuifolia has been used as an antipyretic, detoxication, and anti-inflammatory herb tea in Penghu Island, Taiwan. This study investigated the effects of G. tenuifolia ethanolic extract (GTE) on the formation of RANKL-activating osteoclasts and expression of signaling pathways using a RAW264.7 ...

Bone marrow is the main hematopoietic organ of adults. There, hematopoietic stem cells from which all hematopoietic lineages can be generated are preferentially homing. Importantly, bone provides niches for early B cell differentiation and survival of long-lived plasma cells that produced antibodies. Thus, that perturbing bone homeostasis might impact B cell function and antibody production is a highly relevant hypothesis for patients receiving antiresorptive drugs.<p clas...