Bone Resorption Process Research Articles

Quasi-3D Cytoskeletal Dynamics of Osteocytes under Fluid Flow

Osteocytes respond to dynamic fluid shear loading by activating various biochemical pathways, mediating a dynamic process of bone formation and resorption. Whole-cell deformation and regional deformation of the cytoskeleton may be able to directly regulate this process. Attempts to image cellular deformation by conventional microscopy techniques have been hindered by low temporal or spatial resolution. In this study, we developed a quasi-three-dimensional microscopy technique that enabled us to simultaneously visualize an osteocyte's traditional bottom-view profile and a side-view profile at high temporal resolution. Quantitative analysis of the plasma membrane and either the intracellular actin or microtubule (MT) cytoskeletal networks provided characterization of their deformations over time. Although no volumetric dilatation of the whole cell was observed under flow, both the actin and MT networks experienced primarily tensile strains in all measured strain components. Regional heterogeneity in the strain field of normal strains was observed in the actin networks, especially in the leading edge to flow, but not in the MT networks. In contrast, side-view shear strains exhibited similar subcellular distribution patterns in both networks. Disruption of MT networks caused actin normal strains to decrease, whereas actin disruption had little effect on the MT network strains, highlighting the networks' mechanical interactions in osteocytes.

C-Maf and you won’t see fat

Osteoporosis is a common, age-related bone disease that results from an imbalance between the processes of bone formation and bone resorption, resulting in reduced bone mass and increased risk of fracture. Mesenchymal stem cells have the capacity to differentiate into osteoblastic and adipogenic lineages; recent research suggests that the switch between these two fates may be key to the decreased bone density that occurs with aging. In this issue, Nishikawa et al. demonstrate that the basic leucine-zipper transcription factor Maf (also known as c-Maf) is central to osteoblast lineage commitment. In addition, they find that increased oxidative stress - as occurs with aging - decreases Maf expression. This work advances understanding of the transcriptional regulation of cell fate decisions and may help direct the development of new therapies to fight age-related bone loss.

The combination of miacalcic, calcium lactate, and vitamin C as postextracted alveolar bone resorption inhibitor

Background: Tooth extraction can cause alveolar resorption, and will reduce the denture retention. The process of bone resorption looks like the process of osteoporosis. Calcium and vitamin D supplementation is the rational therapy for minimizing bone loss. Miacalcic is the drug of choice for osteporotic patient. Purpose: This study is aimed to know whether the combination of miacalcic, calcium lactate, and vitamin C are effective in inhibiting post extracted alveolar resorption. Methods: Thirty three healthy postmenopausal women were chosen as samples and they were classified randomly into control group (without treatment), 1st experiment group (treatment was started 3 months post extraction), and 2nd experiment group (treatment was started at the 2nd day post extraction). The treatment was done by giving miacalcic nasal spray, calcium lactate 500 mg and vitamin C 100 mg tablets every morning in 10 days every month for 3 months. X-ray photo of the post extracted area were taken an hour, 3 months, and 6 months post-extraction. Results: After 6 month, there was significant difference in buccolingual thickness decreasing among three groups (p<0.05). The maximum mean difference of buccolingual thickness decreasing was 0.72 mm, between control and 2nd experiment groups. There was no significant difference about decreasing bone density among them (p>0.10). The maximum difference of the mean of density decreasing was 1,906 g/cm2/mm between control and 2nd experiment groups. The increasing density mostly occurred in the 2nd experiment group. Conclusion: The combination of miacalcic, calcium lactate, and vitamin C are effective for inhibiting alveolar resorption, although statistically there was no significant difference about bone density decreasing. The sooner this treatment is given the better result will be achieved.Latar belakang: Pencabutan gigi menyebabkan resorpsi tulang alveolaris, dan akan mengurangi retensi geligi tiruan. Proses resorpsi tulang alveol pada osteoporosis mirip dengan proses resorpsi tulang pada penyembuhan luka bekas pencabutan. Miacalcic adalah obat utama untuk penderita osteoporosis. Kalsium dan vitamin D merupakan terapi yang rasional untuk meminimalkan resorpsi tulang. tujuan: Membuktikan apakah kombinasi miacalcic, kalsium laktat, and vitamin C juga efektif menghambat resorpsi tulang alveol pasca pencabutan. Metode: Sampel 33 wanita postmenopause yang sehat, terbagi secara acak ke dalam kelompok kontrol (tanpa perlakuan), kelompok eksperimen 1 (perlakuan mulai 3 bulan pasca pencabutan) dan kelompok eksperimen 2 (perlakuan mulai hari kedua pasca pencabutan). Perlakuannya yaitu: pemberian miacalcic semprot hidung, tablet kalsium laktat 500 mg dan vitamin C 100 mg setiap pagi, 10 hari dalam sebulan, selama tiga bulan. Foto sinar-X dari regio pasca pencabutan dibuat satu jam, 3 bulan, dan 6 bulan pasca pencabutan. Hasil: 6 bulan pasca-cabut, ada beda bermakna perihal selisih tebal bukolingual tulang alveol antar ketiga kelompok (p<0,05). Rerata penurunan ketebalan ini maksimal sebanyak 0.72 mm, antara kelompok kontrol dan kelompok eksperimen 2. Penurunan kepadatan tulang antar ketiga kelompok tidak bermakna (p>0,10). Beda maksimum rerata kepadatan tulang antara kelompok kontrol dan kelompok eksperimen 2 sebesar 1,906 g/cm2/mm. Peningkatan kepadatan terbanyak dialami anggota kelompok eksperimen 2. Kesimpulan: Kombinasi miacalcic, kalsium laktat, vitamin C efektif menghambat resorpsi tulang alveolaris, walaupun secara statistik beda penurunan kepadatan tidak bermakna. Makin awal pemberian perlakuan, hasilnya akan lebih baik.

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

The aim of this study is to identify the exact mechanism(s) by which cytoskeletal structures are modulated during bone resorption. In this study, we have shown the possible role of different actin-binding and signaling proteins in the regulation of sealing ring formation. Our analyses have demonstrated a significant increase in cortactin and a corresponding decrease in L-plastin protein levels in osteoclasts subjected to bone resorption for 18 h in the presence of RANKL, M-CSF, and native bone particles. Time-dependent changes in the localization of L-plastin (in actin aggregates) and cortactin (in the sealing ring) suggest that these proteins may be involved in the initial and maturation phases of sealing ring formation, respectively. siRNA to cortactin inhibits this maturation process but not the formation of actin aggregates. Osteoclasts treated as above but with TNF-α demonstrated very similar effects as observed with RANKL. Osteoclasts treated with a neutralizing antibody to TNF-α displayed podosome-like structures in the entire subsurface and at the periphery of osteoclast. It is possible that TNF-α and RANKL-mediated signaling may play a role in the early phase of sealing ring configuration (i.e. either in the disassembly of podosomes or formation of actin aggregates). Furthermore, osteoclasts treated with alendronate or αv reduced the formation of the sealing ring but not actin aggregates. The present study demonstrates a novel mechanistic link between L-plastin and cortactin in sealing ring formation. These results suggest that actin aggregates formed by L-plastin independent of integrin signaling function as a core in assembling signaling molecules (integrin αvβ3, Src, cortactin, etc.) involved in the maturation process.

The role of RANKL and MMP-9 in the bone resorption caused by ameloblastoma

Ameloblastoma, a common odontogenic tumor located in jaws, generally leads to severe damage to patient's complexion and masticatory function. To expand in jaws, ameloblastoma must have a mechanism of resorbing the surrounding bone. Our objective was to explore the bone-resorption mechanism of ameloblastoma by observing the role of Receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinase-9 (MMP-9) in the bone-resorption process. In the study, the expression of RANKL and MMP-9 in ameloblastoma was detected using immunohistochemistry (IHC) and RT-PCR. Then, co-culture system of ameloblastoma cells and bone marrow cells from neonatal rabbit was erected to observe the potential of ameloblastoma cells to induce osteoclastogenesis. Finally, the induced osteoclasts were used for in vitro bone-resorption assay. In the co-culture system and the bone-resorption assay, the selective inhibitor of RANKL and MMP-9, osteoprotegerin (OPG) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were, respectively, used for observing the role of RANKL and MMP-9. The expression of RANKL and MMP-9 in ameloblastoma was confirmed. Ameloblastoma cells were found to induce bone marrow cells from neonatal rabbit differentiate into osteoclasts with bone-resorption activity. In addition, OPG was found to, respectively, have markedly inhibitory effect on osteoclastogenesis (P<0.01), and slightly inhibitory action on bone resorption (P<0.05). Ameloblastoma cells had the potential to induce osteoclastogenesis. Moreover, RANKL played an essential role in the in vitro osteoclast formation and bone resorption induced by ameloblastoma cells.

Current and emerging therapies for the treatment of osteoporosis.

Osteoporosis represents a weakening of bone tissue due to an imbalance in the dynamic processes of bone formation and bone resorption that are continually ongoing within bone tissue. Most currently available osteoporosis therapies are antiresorptive agents. Over the past decade, bisphosphonates, notably alendronate and risedronate, have become the dominant agents with newer bisphosphonates such as ibandronate and zoledronic acid following a trend of less frequent dosing regimens. Synthetic estrogen receptor modulators (SERMs) continue to be developed as drugs that maintain the bone-protective effects of estrogen while avoiding its associated adverse side effects. Currently available agents of this class include raloxifene, the only SERM available in the United States (US), and lasofoxifene and bazedoxifene, available in Europe. Calcitonin, usually administered as a nasal spray, completes the list of currently approved antiresorptive agents, while parathyroid hormone analogs represent the only anabolic agents currently approved in both the US and Europe. Strontium ranelate is an additional agent available in Europe but not the US that has both anabolic and antiresorptive activity. New agents expected to further expand therapeutic options include denosumab, a monoclonal antibody inhibitor of the resorptive enzyme cathepsin K, which is in the final stages of Food and Drug Administration approval. Other agents in preclinical development include those targeting specific molecules of the Wnt/β-catenin pathway involved in stimulating bone formation by osteoblast cells. This review discusses the use of currently available agents as well as highlighting emerging agents expected to bring significant changes to the approach to osteoporosis therapy in the near future.

Erythrina variegata extract exerts osteoprotective effects by suppression of the process of bone resorption

Our previous study showed that Erythrina variegata L. (EV) inhibited bone loss and improved bone properties in ovariectomised rats. The purpose of the present study is to investigate the potential mechanism involved in mediating the osteoprotective actions of EV. Female Sprague-Dawley rats were fed a phyto-oestrogen-free diet and subjected to either ovariectomy or a sham operation. Ovariectomised rats were treated with genistein (40 mg/kg) as well as low (200 mg/kg), medium (500 mg/kg) or high (1000 mg/kg) doses of EV extract. Bone properties and mRNA expressions were evaluated by micro-computed tomography and quantitative RT-PCR, respectively. Osteoclast differentiation in RAW 264.7 cells was studied by tartrate-resistant acid phosphatase (TRAP) staining. High doses of EV could decrease urinary Ca and P excretion, maintain serum Ca and P level, and exert beneficial effects on the micro-structure and morphology of trabecular bone and cortical bone in ovariectomised rats. EV suppressed the up-regulation of cathepsin K mRNA and the down-regulation of osteoprotegrin mRNA in the tibia of ovariectomised rats. TRAP-positive cell numbers were significantly decreased in receptor activator of nuclear factor-κB ligand (RANKL)-induced RAW 264.7 cells when co-cultured with EV extracts. The present study indicated that the protective effects of EV on bone properties in ovariectomised rats are likely to be mediated by its inhibitory actions on the process of bone resorption via the suppression of osteoclast differentiation and maturation.

Study of the mechanisms by which Sambucus williamsii HANCE extract exert protective effects against ovariectomy-induced osteoporosis in vivo

The purpose of this study is to investigate the dose-dependent effects of SWH on bone properties and the mechanism involved in mediating the osteoprotective actions of SWH. The results indicated that SWH could improve bone properties by inhibiting the process of bone resorption and stimulating the process of bone formation. Our previous study showed that Sambucus williamsii HANCE (SWH) improved trabecular bone mass and cortical bone strength in ovariectomized (OVX) rats. The purpose of this study is to investigate the dose-dependent effects of SWH on bone properties and the mechanism involved in mediating the osteoprotective actions of SWH. Three-month-old C57BL/6J mice were fed a phytoestrogen-free diet and subjected to either ovariectomy or sham operation. OVX mice were treated with genistein (50 mg/kg), or a low (200 mg/kg), medium (500 mg/kg), or high (1,000 mg/kg) dose of SWH extract. SWH could dose-dependently decrease urinary Ca excretion and increase serum Ca level in OVX mice. It could increase tibial bone mineral density and exert beneficial effects on the microarchitecture of trabecular bone in the OVX mice. SWH suppressed the ovariectomy-induced expression of Cbfa1 mRNA and cathepsin K mRNA and enhanced the ratio of OPG/RANKL mRNA expression in the tibia. In vitro study showed that SWH dramatically reduced the number of TRAP-positive cells in RANKL-induced RAW 264.7 cells. The present study indicated that SWH could improve bone properties by inhibiting the process of bone resorption and stimulating the process of bone formation.

Structural, cellular, and molecular evaluation of bone erosion in experimental models of rheumatoid arthritis: Assessment by μCT, histology, and serum biomarkers

Bone erosion is a clinical endpoint for various diseases including rheumatoid arthritis. In this paper, we used rodent arthritis models with severe bone erosion to examine the structural, cellular, and molecular aspects of the inflammation-driven bone resorption process. Our data show that bone loss is observed only in chronically, severely inflamed joints. The most severely affected anatomic sites were the metatarsal phalangeal joint and tarsal bones of the paw. The magnitude of the inflammation-driven bone erosion was dependent on both the duration of inflammatory response and the severity of the joint swelling response. The application of micro-computed tomography well demonstrated the therapeutic benefit of anti-IL-17A in protection of bones from erosion. Alterations in the cellular profile of the joint occurred prior to any major structural deterioration of the bone. Receptor activator for nuclear factor κB ligand, a potent inducer of osteoclast differentiation and bone resorption, was elevated in animals coincident with severe arthritis initiation. The experimental approaches and concepts outlined in this paper provide a valuable process to evaluate and quantify therapies that modulate rodent arthritis-associated bone-erosion models.

Targeting RANK/RANKL in the Treatment of Solid Tumours and Myeloma

Cancers which damage the human skeleton include multiple myeloma, where the primary tumour colonises bone directly, or breast and prostate cancer, where malignant cells travel from the primary tumour to form clonal outgrowths within the bone. Owing to the interaction of tumour cells with those normally found in the bone microenvironment, such as osteoclasts and osteoblasts, these cancers affect the closely linked processes of bone formation and resorption. As a result, these twin processes contribute to the clinical manifestations of cancer metastasis, including bone pain and pathological fractures. A critical component of physiologically normal bone remodelling, the RANK/RANKL/OPG pathway, has been implicated in the formation of osteolytic, and possibly osteoblastic, lesions, which characterise the bone disease associated with these malignancies. In these cancers that affect the skeleton in this way the abnormally regulated RANK/RANKL system appears to be the final effector pathway. As a result, there has been much research focused upon targeting these molecules using OPG constructs, peptidomimetics, soluble receptor constructs and antibodies to RANKL, in pre-clinical studies. The success of these studies has paved the way for a clinical programme, the success of which is likely to lead to a new therapeutic approach to treating cancers that develop in the skeleton.

High‐Throughput Yeast Screen to Identify Vacuolar H+‐ATPase subunit a specific inhibitors

Vacuolar H+‐ATPases (V‐ATPases) are multi‐subunit proteins critical for acidification of intracellular compartments. V‐ATPases are important for biological processes such as bone resorption and disease related processes including metastasis. V‐ATPase localization is determined by the subunit a isoform. There are four a isoforms in humans, a1‐a4. V‐ATPases at the plasma membrane of osteoclasts have a3 and those at the plasma membrane of certain renal cells have a4. Genetic defects in a3 and a4 lead to osteopetrosis and renal tubular acidosis, respectively. We would like to exploit the specificity of a isoform function to develop isoform specific inhibitors that can be used as therapeutics for diseases. A high‐throughput screen will be developed in which each of the human a isoforms will be expressed in a yeast strain lacking the endogenous a subunit genes. These yeast strains will be grown in the presence of compounds from small molecule libraries. Isoform‐specific inhibitors will be identified by their ability to selectively block growth at neutral pH in yeast strains expressing the appropriate a isoforms. Thus far our experiments indicate that expression of the human a subunit alone does not complement the loss of the yeast a subunits. Thus, to develop the inhibitor screen we must determine the minimal number of mammalian V0 subunits necessary to have a functional V‐ATPase containing the human a subunit.

Lipoteichoic acid from Staphylococcus aureus attenuates differentiation of pre-osteoclast into mature osteoclast (136.26)

Abstract Bacterial virulence factors regulate differentiation and functions of osteoclasts, which mediate the bone-resorptive process. Here, we investigated the effect of a major cell wall virulence factor of Gram-positive bacteria, lipoteichoic acid (LTA), on the osteoclast differentiation. Highly-pure and structurally-intact LTA was prepared from Staphylococcus aureus through sequential application of organic solvent extraction and hydrophobic-interaction column chromatography followed by ion-exchange column chromatography. Osteoclast precursors were prepared from C57BL/6 mouse bone marrow cells using M-CSF and RANKL. Staphylococcal LTA suppressed the differentiation of osteoclast precursors to mature osteoclasts concordantly with an inhibition of the bone-resorptive capacity. Meanwhile, LTA augmented the phagocytic and inflammatory potential of the pre-osteoclasts. The LTA inhibition of osteoclast differentiation appears to be mediated through Toll-like receptor 2 (TLR2), and interestingly both MyD88-dependent and -independent signaling pathways. Furthermore, LTA reduced phosphorylation of ERK and JNK during the osteoclast differentiation process followed by a decreased DNA-binding activity of AP-1. Conclusively, our results suggest that LTA from S. aureus attenuates the differentiation of pre-osteoclast to mature osteoclast through TLR2 with partial involvement of MyD88 signaling pathways.

PTH battles TGF-β in bone

Bone remodelling in vertebrates is coordinately regulated by the opposing effects of parathyroid hormone (PTH) and transforming growth factor-beta (TGF-beta). PTH couples the processes of bone resorption and formation by enforcing simultaneous internalization of TGF-beta type II receptor (TbetaRII) and PTH type 1 receptor (PTH1R), which attenuates both TGF-beta and PTH signalling in vivo.

Of mice and (wo)men: Mouse models of breast cancer metastasis to bone

Of mice and (wo)men: Mouse models of breast cancer metastasis to bone

Finite Element Analysis of 2 Immediate Loading Systems in Edentulous Mandible: Rigid and Semirigid Splinting of Implants

The objective of this study was to evaluate the stress on the cortical bone around single body dental implants supporting mandibular complete fixed denture with rigid (Neopronto System-Neodent) or semirigid splinting system (Barra Distal System-Neodent). Stress levels on several system components were analyzed through finite element analysis. Focusing on stress concentration at cortical bone around single body dental implants supporting mandibular complete fixed dentures with rigid (Neopronto System-Neodent) or semirigid splinting system (Barra Distal System-Neodent), after axial and oblique occlusal loading simulation, applied in the last cantilever element. The results showed that semirigid implant splinting generated lower von Mises stress in the cortical bone under axial loading. Rigid implant splinting generated higher von Mises stress in the cortical bone under oblique loading. It was concluded that the use of a semirigid system for rehabilitation of edentulous mandibles by means of immediate implant-supported fixed complete denture is recommended, because it reduces stress concentration in the cortical bone. As a consequence, bone level is better preserved, and implant survival is improved. Nevertheless, for both situations the cortical bone integrity was protected, because the maximum stress level findings were lower than those pointed in the literature as being harmful. The maximum stress limit for cortical bone (167 MPa) represents the threshold between plastic and elastic state for a given material. Because any force is applied to an object, and there is no deformation, we can conclude that the elastic threshold was not surpassed, keeping its structural integrity. If the force is higher than the plastic threshold, the object will suffer permanent deformation. In cortical bone, this represents the beginning of bone resorption and/or remodeling processes, which, according to our simulated loading, would not occur.

Proteomics in bone research

Osteoporosis is prevalent among the elderly and is a major cause of bone fracture in this population. Bone integrity is maintained by the dynamic processes of bone resorption and bone formation (bone remodeling). Osteoporosis results when there is an imbalance of the two counteracting processes. Bone mineral density, measured by dual-energy x-ray absorptiometry has been the primary method to assess fracture risk for decades. Recent studies demonstrated that measurement of bone turnover markers allows for a dynamic assessment of bone remodeling, while imaging techniques, such as dual-energy x-ray absorptiometry, do not. The application of proteomics has permitted discoveries of new, sensitive, bone turnover markers, which provide unique information for clinical diagnosis and treatment of patients with bone diseases. This review summarizes the recent findings of proteomic studies on bone diseases, properties of mesenchymal stem cells with high expansion rates and osteoblast and osteoclast differentiation, with emphasis on the role of quantitative proteomics in the study of signaling dynamics, biomarkers and discovery of therapeutic targets.

Role of chemerin/CMKLR1 signaling in adipogenesis and osteoblastogenesis of bone marrow stem cells

Maintenance of healthy bone mass requires a well-coordinated balance between the ongoing processes of bone formation and bone resorption. Bone-forming osteoblasts derive from resident adult stem cells within bone marrow called bone marrow stromal cells (BMSCs). These BMSCs are multipotent and also can give rise to adipocytes, which do not contribute directly to bone formation but may influence bone remodeling through the release of bioactive signaling molecules. Chemerin is a novel adipocyte-derived signaling molecule that promotes adipocyte differentiation. In this study we examined the role of chemerin and the cognate receptors CMKLR1 and CCRL2 as determinants of osteoblast and adipocyte differentiation of the preosteoblast 7F2 cell line and of primary BMSCs. Expression and secretion of chemerin increased dramatically with adipocyte differentiation of these cells. Functionally, knockdown of chemerin or CMKLR1 expression using RNA interference abrogated adipocyte differentiation, clonal expansion, and basal proliferation of BMSCs. In contrast, knockdown of either gene was associated with increased osteoblast marker gene expression and mineralization in response to osteoblastogenic stimuli. Forced expression of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) induced chemerin expression and partially rescued the loss of adipogenesis associated with chemerin or CMKLR1 knockdown in BMSCs. Taken together, these data support a novel role for chemerin/CMKLR1 signaling in regulating adipogenesis and osteoblastogenesis of bone marrow-derived precursor cells. These data reveal a potential role for this signaling pathway as a modulator of bone mass.

Evidences of the cooperative role of the chemokines CCL3, CCL4 and CCL5 and its receptors CCR1+ and CCR5+ in RANKL+ cell migration throughout experimental periodontitis in mice

Periodontal disease (PD) is characterized by the inflammatory bone resorption in response to the bacterial challenge, in a host response that involves a series of chemokines supposed to control cell influx into periodontal tissues and determine disease outcome. In this study, we investigated the role of chemokines and its receptors in the immunoregulation of experimental PD in mice. Aggregatibacter actinomycetemcomitans-infected C57Bl/6 (WT) mice developed an intense inflammatory reaction and severe alveolar bone resorption, associated with a high expression of CCL3 and the migration of CCR5+, CCR1+ and RANKL+ cells to periodontal tissues. However, CCL3KO-infected mice developed a similar disease phenotype than WT strain, characterized by the similar expression of cytokines (TNF-α, IFN-γ and IL-10), osteoclastogenic factors (RANKL and OPG) and MMPs (MMP-1, MMP-2, MMP-3, TIMP-1 and TIMP-3), and similar patterns of CCR1+, CCR5+ and RANKL+ cell migration. The apparent lack of function for CCL3 is possible due the relative redundancy of chemokine system, since chemokines such as CCL4 and CCL5, which share the receptors CCR1 and CCR5 with CCL3, present a similar kinetics of expression than CCL3. Accordingly, CCL4 and CCL5 kinetics of expression after experimental periodontal infection remain unaltered regardless the presence/absence of CCL3. Conversely, the individual absence of CCR1 and CCR5 resulted in a decrease of leukocyte infiltration and alveolar bone loss. When CCR1 and CCR5 were simultaneously inhibited by met-RANTES treatment a significantly more effective attenuation of periodontitis progression was verified, associated with lower values of bone loss and decreased counts of leukocytes in periodontal tissues. Our results suggest that the absence of CCL3 does not affect the development of experimental PD in mice, probably due to the presence of homologous chemokines CCL4 and CCL5 that overcome the absence of this chemokine. In addition, our data demonstrate that the absence of chemokine receptors CCR1+ and CCR5+ attenuate of inflammatory bone resorption. Finally, our data shows data the simultaneous blockade of CCR1 and CCR5 with MetRANTEs presents a more pronounced effect in the arrest of disease progression, demonstrating the cooperative role of such receptors in the inflammatory bone resorption process throughout experimental PD.

Inflammation, Osteoporosis and Atherosclerosis: The Tsimtsoum Concept

There is evidence that the high intake of � 6 and low intake of � 3 fatty acids from the diet contribute to the development of CVD as well as of osteoporotic hip fractures. Increased intake of fruits, vegetables, legumes and nuts that are rich in � 3 fatty acids (alpha-linolenic acid) has recently been found to be protective against CVD and osteoporosis, which raises the possibility that these foods and their nutrients may protect against CVD and hip fracture, and may provide better quality of life. Increased risks in co-twins without an index diagnosis suggest that genetic factors and genes/diet interactions may explain the association of CVD with osteoporotic fractures. There is evidence that Western diet rich in refined carbohydrates (coke drinks, biscuits, cakes, ice creams), trans fat, high � 6 / low � 3 fats, deficiencies in soluble fibers and antioxidants can enhance the expression of about 125 genes, the majority of which are pro-inflammatory; there is increase in AP-1, Egr-1 and NFkB, that are transcription factors for inflammation. It is possible that these pro-inflammatory factors increase risk of osteoporosis as well as of atherothrombosis, resulting into hip fractures and CVD, respectively. Calcification of vascular walls shares similarities with bone formation and resorption processes; in particular, bisphosphonates are known to not only decrease the progression of osteoporosis, but also to prevent the development of atherosclerosis, thereby reducing total mortality rates. On the other hand, cholesterol-lowering statins are anti-inflammatory and reduce risk of CVD and osteoporotic fractures.

Clinical utility of biochemical bone turnover markers in children and adolescents with osteosarcoma

Biochemical markers of bone turnover reflecting the intensity of all bone remodeling processes in skeleton are important for fast and non-invasive assessment of bone formation and resorption processes. They can be used in terms of both physiological and pathological states. The aim of this study was to investigate if bone metabolism markers can be clinically useful for monitoring of treatment in children and adolescents with osteosarcoma. The study consisted of 55 patients (median age 15 years) with osteosarcoma and 60 healthy age matched counterparts. Serum bone turnover markers (bone alkaline phosphatase - BALP, osteocalcin - OC and C-terminal telopeptide of type I collagen - CTX) were analyzed by immunoenzymatic methods in patients at time of diagnosis, during treatment and after therapy. We observed that before treatment the concentration of OC in patients with osteosarcoma was significantly lower (p<0.05) compared to that obtained in healthy children, however, BALP and CTX were at a similar level. During chemotherapy the values of bone formation and resorption markers significantly decreased by about 20-30%. After therapy we observed different concentrations of all bone turnover markers in patients with favorable and unfavorable prognosis. Median values of OC and BALP were over twofold higher in patients with progression as compared to patients with remission of disease (p<0.01 and p<0.001, respectively). Patients with poor prognosis had also higher serum concentration of bone resorption marker in comparison to patients with remission (p<0.01). Presented results suggest that bone turnover markers identify changes in bone metabolism in patients with osteosarcoma during anticancer therapy. These markers due to the non-invasive methods and their specificity might be useful in monitoring of clinical treatment of osteosarcoma patients.