Bone Abstracts

Background: Alzheimer’s dementia (AD) and osteoporosis (OP) are common and parallel ageing and frequently coexist in an ageing population. Low BMD appears related to increased risk of AD. Various clinical conditions have been shown to alter acetylcholine (Ach) signalling and affect bone. Ach receptor (AchR) subunits and Ach esterase (AchE) are expressed in bone. Presynaptic Botox inhibit Ach release and impair bone healing and decrease bone mineral content. Poliomyelitis ...

Differentiation of osteoclast progenitor cells into mononucleated TRAcP+ pre-osteoclasts occurs in the bone marrow. But how are these cells dispatched to the future bone resorption sites? We hypothesized that the collagen type III/I-rich reticulin network of the bone marrow might provide a structural framework for localization and migration of differentiating pre-osteoclasts towards the bone surface. Therefore, adjacent sections from decalcified paraffin-embedded iliac crest b...

Bone remodeling is a crucial process to maintain a healthy bone structure in order to avoid diseases like osteoporosis or osteopetrosis. Osteoclasts contribute to this process by resorbing old and brittle bone allowing osteoblasts to renew the bone substance. During resorption osteoclasts rearrange their actin cytoskeleton by forming an F-actin ring generating a resorptive cavity on the bone surface. Recently, we reported that the F-actin binding protein SWAP-70 regulates oste...

In light of prolonged life expectancy, the need for biomaterials that govern bone regeneration increases. Improved bone regeneration and osseointegration can be achieved by funtionalizing implant materials. The extracellular matrix (ECM) affects differentiation of bone cells and is critical for bone regeneration. Here we assessed the role of the natural occurring bone ECM glycosaminoglycans (GAGs) hyaluronan (HA) and chondroitin sulfate (CS), and their sulfated derivatives, on...

Osteoclast (OC)-mediated bone destruction is a key feature of rheumatoid arthritis (RA). In RA synovial tissue a reduced density of catecholaminergic nerve fibres has been observed. Studies on sweat gland innervation proved that catecholaminergic fibres have the ability to undergo a phenotypic transition to cholinergic nerves. The sympathetic neurotransmitters norepinephrine (NE), acetylcholine (ACh), and vasoactive intestinal peptide (VIP) affect osteoclastogenesis oppositely...

Epidemiological and experimental data indicates that cadmium creates a risk of bone damage even at low exposure. Our recent findings suggest that this heavy metal may affect bone via destroying the receptor activator of nuclear factor (NF)-κβ (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system balance that plays a key role in the regulation of bone metabolism. The aim of this study was to investigate whether low-level exposure to cadmium, corresponding to low lif...

Bone is constantly being molded and shaped by the action of osteoclasts and osteoblasts. A proper equilibrium between both cell types metabolic activities is required to ensure an adequate skeletal tissue structure, and it involves resorption of old bone and formation of new bone tissue. It is reported that treatment with antiepileptic drugs (AEDs) can elicit alterations in skeletal structure, in particular in bone mineral density. Nevertheless, the knowledge regarding the eff...

Hydroxyapatite (HA) has been widely used as a biocompatible ceramic in many areas of medicine, mainly for contact with bone tissue, due to its resemblance to mineral bone. Owing to the nanofeatures of bone tissue, new nano-HA based materials are among the most promising challenges in bioactive ceramics. Recently, it was observed that fluoroquinolones have the ability to interfere with osteoclastogenesis, in standard polystyrene cell culture plates. The aim of this work is to a...

Despite its rigid structure, bone is a dynamic tissue that is in constant remodeling. This process requires the action of the bone-resorbing osteoclasts and the bone-synthesing osteoblasts. One of the adverse effects attributed to some antihypertensive agents is the ability to alter normal bone metabolism. However, their effective actions on human bone cells remain to be clarified. In this work, the effects of five calcium channel blockers, a class of antihypertensive drugs (A...

Osteoclasts are cells specialized for resorption of calcified tissue. Osteoclasts are formed from precursor cells of monocyte lineage under the control of receptor activator of nuclear factor kappaB ligand (RANKL). Mitogen- and stress-activated protein kinase 1 (MSK1) has been reported to be an important regulator of immune response and mitogenic signaling. In this study, we for the first time found that MSK1 was activated by RANKL in osteoclast precursor, bone marrow macropha...

Osteoporosis is an age related disease characterised by a progressive decrease of bone mineral density and loss of bone quality. Twin studies show that genetic component contributes up to 85% of the BMD variability of population. Surprisingly little variability of BMD can be explained by genetic polymorphisms (~2.9%). This highlights the complex genetic architecture and suggests that many other molecular processes and genes have to be involved. Our previous research showed tha...

Osteoclasts are produced by fusion of pre-osteoclasts derived from stem cells of the monocyte/macrophage lineage in the presence of receptor activator of NF-κB ligand (RANKL) produced by osteoblasts. The phytoestrogens; genistein and daidzein, which are isoflavones found in Leguminosae such as soybeans, are currently being investigated for prevention of postmenopausal osteoporosis. Some polyunsaturated fatty acids (PUFAs) have been shown to exert a bone protectiv...

RANKL induced osteoclastogenesis is mediated by several transcription factors such as NF-κB, AP-1 and Nfatc1. We have found that also cysteine proteinases are involved in the signaling pathway downstream RANK. Thus, cystatin C, Z-RLVG-CHN2 (the sequence of which is based upon one of the enzyme inhibitory domains in cystatin C) and the fungal molecule E-64 – inhibit RANKL induced mouse and human osteoclast formation in vitro (Strålberg et ...

Infections within or in the vicinity of the skeleton induce osteolytic diseases such as periodontitis, septic arthritis, osteomyelitis. Although host production of osteotropic cytokines is crucial, the precise mechanism by which pathogen associated molecular patterns induce osteoclastogenesis and bone loss is not fully understood. Recognition of these molecules by pattern recognition receptors is highly preserved through evolution with trans-membrane Toll-like receptor (TLR) f...

β-tricalcium phosphate (β-TCP) biomaterials have been approved for the repair of osseous defects. However, in large defects, the substitution of biomaterial by authentic bone is inadequate to provide sufficient long-term mechanical stability. We aimed to develop composites of β-TCP ceramics and receptor activator of nuclear factor κ-B ligand (RANKL) to enhance the formation of osteoclasts thereby stimulating material resorption. RANKL was immobilized on &#9...

Bisphosphonates (BPs) such as zoledronic acid (ZA) are widely used to treat bone diseases. The use of BPs can lead to osteonecrosis of the jaw (ONJ), but it is not clear why in particular the jaw bone is affected. Previously, it was shown that osteoclasts derived from different bone sites have different properties. We hypothesize that BPs have distinct effects on bone-site specific osteoclasts or precursors. To investigate this, female C57BL/6J mice were injected intraperitone...

Recent GWAS have identified variants in the OPTN gene that predispose to Paget’s disease of Bone (PDB), a disease characterised by focal areas of increased bone turnover and enhanced osteoclast activity, suggesting a role for this gene in bone metabolism. The aim of this study was to investigate the role of OPTN in bone metabolism using a mouse model (OptnD477N/D477N) which harbours a D477N point mutation in the polyubiquitin binding ...

OPTN encodes a cytoplasmic protein optineurin which has been shown to play a role in autophagy. Recent GWAS studies have shown that variants within OPTN are associated with the risk of Paget’s disease of bone, a disease characterized by focal areas of increased bone turnover due to increased osteoclast activity, suggesting a possible role of OPTN in the regulation of bone metabolism.The aim of this study was to investigate the role of optineurin in ...

Osteoclast resorption depends on their ability to reorganise their actin cytoskeleton and form the sealing zone. In order to resorb bone, osteoclasts become polarised by condensing their podosomes into a highly dynamic podosomal belt. The podosome turnover is regulated by several factors such as non-receptor tyrosine kinases, small GTPases and actin-binding proteins. The innate immune system responds to viral pathogens. Cytoplasmic double-stranded DNA activates the immune syst...

Familial expansile osteolysis (FEO) is characterised by focal areas of increased bone turnover driven by bone-resorbing osteoclasts. The syndrome is caused by a heterozygous tandem insertion duplication mutation within the signal peptide region of TNFRSF11a (encoding receptor activator of NFκB; RANK). Our recent research has demonstrated that heterotrimeric receptor formation may hold the key to the disease phenotype. We have shown previously that, whilst homozygous overe...

Early-onset Paget’s disease of bone (ePDB), familial expansile osteolysis (FEO) and expansile skeletal hyperphosphatasia (ESH) are related syndromes caused by heterozygous tandem insertion duplication mutations within the signal peptide region of TNFRSF11a (encoding receptor activator of NFκB; RANK). Given that patients are always heterozygous for these mutations we have generated thirteen cell lines to investigate the molecular consequences of these mutations in...

Extracellular nucleotides stimulate both the formation and resorptive activity of osteoclasts. Ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs) hydrolyse extracellular nucleotide triphosphates to their corresponding monophosphate and pyrophosphate (PPi). We investigated if osteoclasts express functional NPPs and whether Enpp1 gene deletion influenced osteoclast formation and activity. Osteoclasts were formed from the bone marrow of 8 and 15 week old knockou...

Introduction: Nitrogen-containing bisphosphonates (N-BPs) can inhibit the differentiation and function of osteoclasts derived from Peripheral Blood Mononuclear cells (PBMCs) in a dose-dependent manner. MUTZ-3 cells are a potentially useful human cell line for studying osteoclast differentiation. The aim of this study was to elucidate the action of N-BPs on MUTZ-3 cells.Methods: Human PBMCs and MUTZ-3 cells were cultured in α-MEM supplemented with he...

Despite its importance, the resorptive surface of osteoclasts has not been directly visualised. We exploited a novel approach that enables us to inspect the substrate-apposed surface of cells. To achieve this, we incubated osteoclasts on vitronectin-coated nail varnish and, afterwards, we dissolved the substrate and visualised the cells resorbing-side up in the scanning electron microscope (SEM). We then employed confocal microscopy to correlate the SEM appearances with the di...