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Bone Destruction (bone + destruction)
Kinds of Bone Destruction Selected AbstractsAggressive and Neglected Basal Cell CarcinomaDERMATOLOGIC SURGERY, Issue 11 2005Ali Asilian MD Background. Basal cell carcinoma (BCC) is the most common cutaneous malignancy and usually has a benign coarse. Rarely, examples of aggressive and neglected types of this tumor are seen. Objective. To present an interesting and dramatic example of how some people neglect their tumors and how devastating the sequelae can be. Methods. We report a 58-year-old man with an extensive BCC and signs of cranial nerve involvement. Results. The patient had a large, infected ulcer on his scalp. He also had skull bone destruction, osteomyelitis, mastoiditis, cranial nerve paralysis, and radiographic features of the skull base and upper cervical soft tissue involvement. Pathologic studies revealed an infiltrating form of BCC. Conclusions. If left untreated and neglected, as in this case, BCC can become inoperable and complicated. ALI ASILIAN, MD, AND BANAFSHE TAMIZIFAR, MD, HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS. [source] A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone lossEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Jaya Goswami Abstract Post-menopausal osteoporosis is considered to be an inflammatory process, in which numerous pro-inflammatory and T-cell-derived cytokines play a bone-destructive role. IL-17A is the signature cytokine of the pro-inflammatory Th17 population and plays dichotomous roles in diseases that affect bone turnover. Although IL-17A promotes bone loss in rheumatoid arthritis, it is protective against pathogen-induced bone destruction in a periodontal disease model. We used a model of ovariectomy-induced osteoporosis (OVX) in IL-17 receptor (IL-17RA),/, mice to evaluate the role of the IL-17A in bone loss caused by estrogen deficiency. Unexpectedly, IL-17RA,/, mice were consistently and markedly more susceptible to OVX-induced bone loss than controls. There were no changes in prototypical Th1, Th2 or Th17 cytokines in serum that could account for increased bone loss. However, IL-17RA,/, mice exhibited constitutively elevated leptin, which further increased following OVX. Consistently, IL-17A and IL-17F treatment of 3T3-L1 pre-adipocytes inhibited adipogenesis, leading to reduced production of leptin. In addition to its role in regulating metabolism and satiety, leptin can regulate bone turnover. Accordingly, these data show that IL-17A negatively regulates adipogenesis and subsequent leptin expression, which correlates with increased bone destruction during OVX. [source] Pathogenesis of haemophilic synovitis: experimental studies on blood-induced joint damageHAEMOPHILIA, Issue 2007L. A. VALENTINO Summary., Hemarthrosis is a common manifestation of haemophilia, and joint arthropathy remains a frequent complication. Even though the exact mechanisms related to blood-induced joint disease have not yet been fully elucidated, it is likely that iron deposition in the synovium induces an inflammatory response that causes not only immune system activation but also stimulates angiogenesis. This process ultimately results in cartilage and bone destruction. Investigating the processes that occur in the early stages of blood-induced joint disease in humans has been very limited. Therefore, the use of haemophilic animal models is critical to augment the understanding of this phenomenon. This article discusses three cellular regulators (p53, p21 and TRAIL) induced in synovial tissue that are important for iron metabolism. A cartilage remodelling programme induced by the release of cytokines and growth factors that result in articular damage is also discussed. Full elucidation of the pathogenesis of haemophilic joint disease is required to identify new avenues for prevention and therapy. [source] Protective role of osteopontin in endodontic infectionIMMUNOLOGY, Issue 1 2010Susan R. Rittling Summary Endodontic infections are polymicrobial infections resulting in bone destruction and tooth loss. The host response to these infections is complex, including both innate and adaptive mechanisms. Osteopontin (OPN), a secreted, integrin-binding protein, functions in the regulation of immune responses and enhancement of leucocyte migration. We have assessed the role of OPN in the host response to endodontic infection using a well-characterized mouse model. Periapical bone loss associated with endodontic infection was significantly more severe in OPN-deficient mice compared with wild-type 3 weeks after infection, and was associated with increased areas of inflammation. Expression of cytokines associated with bone loss, interleukin-1, (IL-1,) and RANKL, was increased 3 days after infection. There was little effect of OPN deficiency on the adaptive immune response to these infections, as there was no effect of genotype on the ratio of bacteria-specific immunoglobulin G1 and G2a in the serum of infected mice. Furthermore, there was no difference in the expression of cytokines associated with T helper type 1/type2 balance: IL-12, IL-10 and interferon-,. In infected tissues, neutrophil infiltration into the lesion area was slightly increased in OPN-deficient animals 3 days after infection: this was confirmed by a significant increase in expression of neutrophil elastase in OPN-deficient samples at this time-point. We conclude that OPN has a protective effect on polymicrobial infection, at least partially because of alterations in phagocyte recruitment and/or persistence at the sites of infection, and that this molecule has a potential therapeutic role in polymicrobial infections. [source] Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signalsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Toru Hiraga Abstract Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Recently, it has been reported that imatinib also targets the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. M-CSF signals are essential for the differentiation of osteoclasts. Bone metastases of breast cancer are frequently associated with osteoclastic bone destruction. Furthermore, several lines of evidence suggest that osteoclasts play central roles in the development and progression of bone metastases. Thus, in the present study, we examined the effects of imatinib on bone metastases of breast cancer. Coimmunoprecipitation assays showed that imatinib inhibited the M-CSF-induced phosphorylation of c-Fms in osteoclast precursor cells as well as the PDGF-induced PDGFR phosphorylation in MDA-MB-231 human breast cancer cells. Imatinib also markedly reduced osteoclast formation in vitro. In contrast, those concentrations of imatinib did not affect osteoblast differentiation. We then examined the effects of imatinib on bone metastases of MDA-MB-231 cells in a nude mouse model. Radiographic and histomorphometric analyses demonstrated that imatinib significantly decreased bone metastases associated with the reduced number of osteoclasts. In support of the notion that the inhibition of c-Fms acts to suppress the development of bone metastases, we found that a specific inhibitor of c-Fms Ki20227 also decreased bone metastases. In conclusion, these results collectively suggest that imatinib reduced bone metastases, at least in part, by inhibiting osteoclastic bone destruction through the blockade of c-Fms signals. Our results also suggest that imatinib may have a protective effect against cancer treatment-induced bone loss. © 2008 Wiley-Liss, Inc. [source] Biochemical markers of bone turnover and bone mineral density in patients with ,-thalassaemia majorINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 1 2005E. Eren Summary In this study, bone formation markers (bone-specific alkaline phosphatase and osteocalcin) and bone resorption markers (pyridinoline and deoxypyridinoline) were analysed. Bone formation, as evidenced by the levels of serum alkaline phosphatase and osteocalcin, did not appear to be impaired, while bone resorption was grossly increased in all patient groups. The decrease of bone mineral density values was more prominent in the lumbar spine, thus making this site particularly interesting for such studies. The patients had significantly lower femoral neck and lumbar spine bone mineral density when compared with control (all p < 0.001). Our conclusion is that, in spite of the severe bone destruction that occurs in thalassaemia major, the fact that bone formation remains intact calls for a more intensive treatment. [source] Necropoli of Pill'e Matta Quartucciu (Cagliari, Sardinia): wild bee and solitary wasp activity and bone diagenetic factorsINTERNATIONAL JOURNAL OF OSTEOARCHAEOLOGY, Issue 3 2009E. Pittoni Abstract During the excavation at the necropolis and the laboratory studies, a variety of damage was found in the human bone remains. This damage included round holes, irregular bone destruction and irregular etching. This can be found especially in the skulls and in the long bones, and sometimes in the vertebrae and on the hands and feet. The exceptionality of this demanded meticulous study in order to define whether it was a diagenetic phenomenon of biological origin. Further studies revealed that the damage to the bones was produced by three kinds of Hymenoptera that build galleries: one of these belongs to the Sphecidae family, the other two to the Halictidae family. During the excavation of a grave it had been observed that a Halictidae had invaded the burial context and consequently contributed to the taphonomic and diagenetic process. The laboratory activities were directed towards the measurement of the damage to the human bone remains in 45 tombs. A histogram shows that the holes are not the result of accidental lesions, and the more frequent percentage values show similarities with the dimensions of holes built by the insects. The observations and the results of the study at the archaeological site enabled me to establish how significant the role of the insects had been, in particular of the Hymenoptera, in modifying the condition of the bone remains. Copyright © 2008 John Wiley & Sons, Ltd. [source] Dendritic Cells at the Osteo-Immune Interface: Implications for Inflammation-Induced Bone Loss,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2007Mawadda Alnaeeli Abstract Within the past decade, the critical roles of T cells and T cell,mediated immunity in inflammation-induced osteoclastogenesis and subsequent bone loss have been extensively studied, thereby establishing the new paradigm of osteoimmunology. Therefore, dendritic cells (DCs), the most potent antigen-presenting cells, responsible for activation of naïve T cells and orchestration of the immune response, became critically situated at the osteo-immune interface. Today, emerging new evidence suggests that DC may be directly involved in inflammation-induced osteoclastogenesis and bone loss, by acting as osteoclast (OC) precursors that can further develop into DC-derived OCs (DDOC) under inflammatory conditions. These findings have tremendous implications, because in addition to DC's important roles in regulating innate and adaptive immunity, a direct contribution by these cells to inflammation-induced bone loss may provide a promising therapeutic target not only for controlling inflammation but also for modulating bone destruction. [source] Gorham-Stout Disease,Stabilization During Bisphosphonate Treatment,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2005Fabian Hammer Abstract A 45-year-old woman presented with recent onset of left-sided chest pain. On clinical examination, these symptoms seemed to be strictly localized to a region that was marked by a long-standing cutaneous erythematous lesion. Laboratory results showed no gross abnormalities. Radiological imaging including conventional X-ray, MRI scans, and 3D CT reconstruction of the rib cage revealed circumscript destruction of the left lateral ribs 9,11. Histological analysis of a rib biopsy showed angiomatous hypervascularization and intracortical fibrosis. In keeping with these findings, the patient's condition was diagnosed as Gorham-Stout disease, a rare condition with localized, often unilateral, bone destruction. Monotherapy with bisphosphonates (pamidronate 30 mg IV every 3 months) was initiated, leading to rapid disappearance of local pain. Follow-up over 24 months documented a stable clinical and radiological picture without evidence of progressive bone destruction. [source] Early Detection of Bone Metastases in a Murine Model Using Fluorescent Human Breast Cancer Cells: Application to the Use of the Bisphosphonate Zoledronic Acid in the Treatment of Osteolytic LesionsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2001Olivier Peyruchaud Abstract A very common metastatic site for human breast cancer is bone. The traditional bone metastasis model requires human MDA-MB-231 breast carcinoma cell inoculation into the left heart ventricle of nude mice. MDA-MB-231 cells usually develop osteolytic lesions 3,4 weeks after intracardiac inoculation in these animals. Here, we report a new approach to study the formation of bone metastasis in animals using breast carcinoma cells expressing the bioluminescent jellyfish protein (green fluorescent protein [GFP]). We first established a subclone of MDA-MB-231 cells by repeated in vivo passages in bone using the heart injection model. On stable transfection of this subclone with an expression vector for GFP and subsequent inoculation of GFP-expressing tumor cells (B02/GFP.2) in the mouse tail vein, B02/GFP.2 cells displayed a unique predilection for dissemination to bone. Externally fluorescence imaging of live animals allowed the detection of fluorescent bone metastases approximately 1 week before the occurrence of radiologically distinctive osteolytic lesions. The number, size, and intensity of fluorescent bone metastases increased progressively with time and was indicative of breast cancer cell progression within bone. Histological examination of fluorescent long bones from B02/GFP.2-bearing mice revealed the occurrence of profound bone destruction. Treatment of B02/GFP.2-bearing mice with the bisphosphonate zoledronic acid markedly inhibited the progression of established osteolytic lesions and the expansion of breast cancer cells within bone. Overall, this new bone metastasis model of breast cancer combining both fluorescence imaging and radiography should provide an invaluable tool to study the effectiveness of pharmaceutical agents that could suppress cancer colonization in bone. [source] Markers of bone destruction and formation and periodontitis in type 1 diabetes mellitusJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 8 2009David F. Lappin Abstract Aim: To determine plasma concentrations of bone metabolism markers in type 1 diabetes mellitus patients and non-diabetic and to evaluate the influence of periodontitis on biomarkers of bone formation in these patient groups. Methods: Plasma concentrations of receptor activator of nuclear factor- ,B ligand (RANKL), osteoprotegerin (OPG), C-terminal telopeptide of type 1 collagen and osteocalcin were measured in type 1 diabetes mellitus patients (n=63) and non-diabetics (n=38) who were also subdivided on the basis of their periodontal status. Results: Diabetics had significantly lower osteocalcin concentrations, lower RANKL to OPG ratios and higher OPG concentrations (as shown by other researchers) than non-diabetics. The ratio of RANKL to OPG was altered by the periodontal status. Osteocalcin had a negative correlation and OPG a positive correlation with the percentage of glycated haemoglobin in the blood. Conclusion: Because, osteocalcin, a biomarker of bone formation, is lower in patients with periodontitis and in patients with type 1 diabetes mellitus with and without periodontitis than in non-diabetics without periodontitis, this might indicate that diabetics are less able to replace bone lost during active bursts of periodontitis and explain the greater severity of disease seen in studies of patients with diabetes. [source] Correlation between early perforation of cover screws and marginal bone loss: a retrospective studyJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 1 2008Nele Van Assche Abstract Aim: This retrospective study aimed to determine the consequence of early cover screw exposure on peri-implant marginal bone level. Material and Methods: Sixty Astra Tech® MicroThread implants installed in partially edentulous jaws were compared: 20 implants were placed following a two-stage procedure and were unintentionally exposed to the oral cavity (two-stage exposed), 20 implants were placed following a two-stage procedure and were surgically exposed after a subgingival healing time of 3,6 months (two-stage submerged), and 20 implants were placed following a one-stage surgical protocol (one-stage). Digital radiographs were taken at implant placement for all implants, and after abutment surgery for the two-stage exposed and two-stage submerged groups or after 3 months for the one-stage group. Bone loss mesially and distally was measured with an on-screen cursor after calibration. Results: Mean bone re-modelling was 1.96 mm (range: 0.2,3.2 mm) around the two-stage exposed implants, 0.01 mm (range: 0.0,0.3 mm) around the two-stage submerged implants and 0.14 mm (range: 0.0,1.2 mm) around the one-stage implants. Conclusion: The unintentional perforation of two-stage implants resulted in significant bone destruction, probably because the biological width was not considered. [source] 5-aminoisoquinolin-1(2H)-one, a water-soluble poly (ADP-ribose) polymerase (PARP) inhibitor reduces the evolution of experimental periodontitis in ratsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 2 2007Rosanna Di Paola Abstract Background: Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischaemia-reperfusion and inflammation. Recent studies have demonstrated that PARP activation plays a crucial role in the pathogenesis of acute periodontal injury. Aim: We have investigated the effect of 5-aminoisoquinolin-1(2H)-one (5-AIQ), a water-soluble PARP inhibitor, in a rat model of periodontitis. Materials and Methods: Periodontitis was induced in rats by placing a 2/0 braided silk ligature around the lower left first molar. At day eight, the gingivomucosal tissue encircling the mandibular first molar was removed for biochemical and histological analysis. Results and Conclusions: Ligation significantly induced an increased neutrophil infiltration and a positive staining for PARP activation. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone destruction. Intraperitonial injection of 5-aminoisoquinolin-1(2H)-one (5-AIQ) (5 mg/kg daily for eight days) significantly decreased all of the parameters of inflammation as described above. This suggests that inhibition of PARP may represent a novel approach for the treatment of periodontal disease. [source] Effect of adoptive transfer of antigen-specific B cells on periodontal bone resorptionJOURNAL OF PERIODONTAL RESEARCH, Issue 2 2006Y. Harada Background and Objectives:, Host immune responses to periodontal pathogens have been considered to contribute to the alveolar bone destruction in periodontitis. However, the role of B lymphocytes in the pathogenesis of periodontal bone loss is not clear. Methods:, We examined the effect of adoptive transfer of antigen-specific B cells from rat spleens on experimental periodontal bone resorption. Donor rats were immunized intraperitoneally (i.p.) with formalin-killed Actinobacillus actinomycetemcomitans. Antigen-specific B cells were prepared from splenocytes by first binding CD43+ cells to Petri dishes coated with anti-CD43 antibody to remove T cells, and non-binding cells were passed through a nylon wool column to deplete accessory cells. The retained cells were then collected and bound to A. actinomycetemcomitans- coated Petri dishes for enrichment of A. actinomycetemcomitans -binding B cells (AAB). A. actinomycetemcomitans non-binding B cells (ANB) and B cells from non-immunized donor rats (NIB) were also collected from these procedures. Each type of B cell was injected into a group of recipient rats that were then orally infected with live A. actinomycetemcomitans. Results:, At termination, the antibody levels to A. actinomycetemcomitans in serum and gingival wash fluids were significantly higher in the recipients transferred with AAB when compared to the recipients transferred with ANB or NIB. A markedly elevated number of antibody-forming cells were observed in the spleens of the recipients transferred with AAB, and these recipient rats also exhibited significantly increased bone resorption when compared to the other groups. Conclusions:, It is suggested that B cells can contribute to periodontal bone resorption and that antigen-triggering of B cells is required for the bone resorption. [source] Single-Agent Pamidronate for Palliative Therapy of Canine Appendicular Osteosarcoma Bone PainJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2007Timothy M. Fan DVM Background:Canine appendicular osteosarcoma (OSA) causes focal bone destruction, leading to chronic pain and reduced quality-of-life scores. Drugs that inhibit pathologic osteolysis might provide additional treatment options for managing cancer-induced bone pain. Aminobisphosphonates induce osteoclast apoptosis, thereby reducing pain associated with malignant osteolysis in human patients with cancer. Hypothesis:Treatment of dogs with pamidronate administered intravenously will alleviate bone pain and reduce pathologic bone turnover associated with appendicular OSA in dogs. Animals:Forty-three dogs with naturally occurring appendicular OSA administered pamidronate intravenously. Methods:Prospective study. Therapeutic responses in dogs treated with pamidronate administered intravenously and nonsteroidal anti-inflammatory drugs (NSAID) were evaluated by using a numerical cumulative pain index score (CPIS), and by quantifying urine N-telopeptide (NTx) excretion and relative primary tumor bone mineral density (rBMD) assessed with dual energy x-ray absorptiometry. In addition, variables, including pamidronate dose, skeletal mass, baseline and change for CPIS, urine NTx and rBMD during treatment, and baseline tumor volume and radiographic pattern were compared between dogs clinically responsive and nonresponsive to pamidronate therapy. Results:Twelve of 43 dogs (28%) had pain alleviation for > 4 months, lasting a median of 231 days. Changes in CPIS and rBMD during treatment were statistically different between responders and nonresponders (P= .046 and .03, respectively). Conclusions and Clinical Importance: Substantiated by reductions in CPIS and increases in rBMD, single-agent pamidronate administered intravenously with NSAID therapy relieves pain and diminishes pathologic bone turnover associated with appendicular OSA in a subset of dogs. [source] Immunization of Macaca fascicularis against experimental periodontitis using a vaccine containing cysteine proteases purified from Porphyromonas gingivalisMOLECULAR ORAL MICROBIOLOGY, Issue 3 2007R. C. Page Introduction:, Periodontitis is a common infectious disease to which Porphyromonas gingivalis has been closely linked, in which the attachment tissues of the teeth and their alveolar bone housing are destroyed. We conducted a study to determine if immunization using a purified antigen could alter the onset and progression of the disease. Methods:, Using the ligature-induced model of periodontitis in Macaca fascicularis, we immunized five animals with cysteine protease purified from P. gingivalis and used an additional five animals as controls. Alveolar bone loss was measured by digital subtraction radiography. Results:, Immunization induced high titers of specific immunoglobuin G serum antibodies that were opsonic. Total bacterial load, levels of P. gingivalis in subgingival plaque and levels of prostaglandin E2 in gingival crevicular fluid were significantly reduced. Onset and progression of alveolar bone loss was inhibited by approximately 50%. No manifestations of toxicity were observed. Conclusions:, Immunization using a purified protein antigen from P. gingivalis inhibits alveolar bone destruction in a ligature-induced periodontitis model in M. fascicularis. [source] Problems in determination of skeletal lead burden in archaeological samples: An example from the First African Baptist Church populationAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 4 2008L.E. Wittmers Jr. Abstract Human bone lead content has been demonstrated to be related to socioeconomic status, occupation and other social and environmental correlates. Skeletal tissue samples from 135 individuals from an early nineteenth century Philadelphia cemetery (First African Baptist Church) were studied by electrothermal atomic absorption spectrometry and X-ray fluorescence for lead content. High bone lead levels led to investigation of possible diagenetic effects. These were investigated by several different approaches including distribution of lead within bone by X-ray fluorescence, histological preservation, soil lead concentration and acidity as well as location and depth of burial. Bone lead levels were very high in children, exceeding those of the adult population that were buried in the cemetery, and also those of present day adults. The antemortem age-related increase in bone lead, reported in other studies, was not evidenced in this population. Lead was evenly deposited in areas of taphonomic bone destruction. Synchrotron X-ray fluorescence studies revealed no consistent pattern of lead microdistribution within the bone. Our conclusions are that postmortem diagenesis of lead ion has penetrated these archaeological bones to a degree that makes their original bone lead content irretrievable by any known method. Increased bone porosity is most likely responsible for the very high levels of lead found in bones of newborns and children. Am J Phys Anthropol, 2008. © 2008 Wiley-Liss, Inc. [source] A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 8 2010Young-Sool Hah Objective Nuclear factor-,B (NF-,B) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-,B, might have antiarthritic effects. Methods An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally. Results In vitro experiments demonstrated that AdA20 suppressed NF-,B activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor , in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus,injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-,B signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-,B. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study. Conclusion These results suggest that using A20 to block the NF-,B pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA. [source] Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiationARTHRITIS & RHEUMATISM, Issue 8 2010Mario M. Zaiss Objective Immune activation triggers bone loss. Activated T cells are the cellular link between immune activation and bone destruction. The aim of this study was to determine whether immune regulatory mechanisms, such as naturally occurring Treg cells, also extend their protective effects to bone homeostasis in vivo. Methods Bone parameters in FoxP3-transgenic (Tg) mice were compared with those in their wild-type (WT) littermate controls. Ovariectomy was performed in FoxP3-Tg mice as a model of postmenopausal osteoporosis, and the bone parameters were analyzed. The bones of RAG-1,/, mice were analyzed following the adoptive transfer of isolated CD4+CD25+ T cells. CD4+CD25+ T cells and CD4+ T cells isolated from FoxP3-Tg mice and WT mice were cocultured with monocytes to determine their ability to suppress osteoclastogenesis in vitro. Results FoxP3-Tg mice developed higher bone mass and were protected from ovariectomy-induced bone loss. The increase in bone mass was found to be the result of impaired osteoclast differentiation and bone resorption in vivo. Bone formation was not affected. Adoptive transfer of CD4+CD25+ T cells into T cell,deficient RAG-1,/, mice also increased the bone mass, indicating that Treg cells directly affect bone homeostasis without the need to engage other T cell lineages. Conclusion These data demonstrate that Treg cells can control bone resorption in vivo and can preserve bone mass during physiologic and pathologic bone remodeling. [source] Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritisARTHRITIS & RHEUMATISM, Issue 6 2010Stephan Blüml Objective To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA). Methods We performed bone marrow transplantations in human TNF,transgenic mice using hematopoietic cells from wild-type, TNFRI,/,, TNFRII,/,, and TNFRI/II,/, mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays. Results Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full-blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF-responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis. Conclusion Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA. [source] Inflammatory arthritis in caspase 1 gene,deficient mice: Contribution of proteinase 3 to caspase 1,independent production of bioactive interleukin-1,ARTHRITIS & RHEUMATISM, Issue 12 2009Leo A. B. Joosten Objective Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro,interleukin-1, (proIL-1,), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. Methods Acute and chronic arthritis were induced in caspase 1,/, mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. Results Surprisingly, caspase 1,/, mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1, were comparable in caspase 1,/, mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1,/, mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1,dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1, concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. Conclusion Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1, production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present. [source] Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatmentARTHRITIS & RHEUMATISM, Issue 10 2009S. Bar-Yehuda Objective Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A3 adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. Methods OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 ,g/kg given twice daily) was initiated. The A3 adenosine receptor antagonist MRS1220 (100 ,g/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O,fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. Results CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-,B signaling pathway, resulting in down-regulation of tumor necrosis factor ,. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. Conclusion CF101 deregulated the NF-,B signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA. [source] Cathepsin K deficiency partially inhibits, but does not prevent, bone destruction in human tumor necrosis factor,transgenic mice,ARTHRITIS & RHEUMATISM, Issue 2 2008Uta Schurigt Objective Cathepsin K is believed to have an eminent role in the pathologic resorption of bone. However, several studies have shown that other proteinases also participate in this process. In order to clarify the contribution of cathepsin K to the destruction of arthritic bone, we applied the human tumor necrosis factor (hTNF),transgenic mouse model, in which severe polyarthritis characterized by strong osteoclast-mediated bone destruction develops spontaneously. Methods Arthritis was evaluated in hTNF-transgenic mice that were either wild-type for cathepsin K (CK+/+), heterozygous for cathepsin K (CK+/,), or deficient in cathepsin K (CK,/,). Arthritic knee joints were prepared for standard histologic assessment aimed at establishing a semiquantitative score for joint destruction and quantification of the area of bone erosion. Additionally, microfocal computed tomography was performed to visualize bone destruction in mice with the different CK genotypes. CK+/+ and CK,/, osteoclasts were generated in vitro, and their proteinase expression profiles were compared by complementary DNA array analysis, real-time polymerase chain reaction, and activity assays. Results Although the area of bone erosion was significantly reduced in hTNF-transgenic CK,/, mice, the absence of cathepsin K did not completely protect against inflammatory bone lesions. Several matrix metalloproteinases (MMPs) and cathepsins were expressed by in vitro,generated CK,/, osteoclasts, without marked differences from CK+/+ osteoclasts. MMP activity was detected in CK,/, osteoclasts, and MMP-14 was localized by immunohistochemistry in inflammatory bone erosions in hTNF-transgenic CK,/, mice, suggesting MMPs as potential contributors to bone destruction. Additionally, we detected a reduction in osteoclast formation in cathepsin K,deficient mice, both in vitro and in vivo. Conclusion The results of our experiments raise doubts about a crucial role of cathepsin K in arthritic bone destruction. [source] Blockade of parathyroid hormone,related protein prevents joint destruction and granuloma formation in streptococcal cell wall,induced arthritisARTHRITIS & RHEUMATISM, Issue 6 2003J. L. Funk Objective To determine whether parathyroid hormone,related protein (PTHrP), an interleukin-1,,inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA. Methods PTHrP expression and the effect of PTHrP 1,34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW),induced arthritis, an animal model of RA. Results As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor,positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1,34. Conclusion These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders. [source] Severe necrotizing stomatitis and osteomyelitis after chemotherapy for acute leukaemiaAUSTRALIAN DENTAL JOURNAL, Issue 3 2009FA Santos Abstract Background:, Leukaemia is a malignant neoplasm characterized by clonal proliferation of white blood cells within the bone marrow. Despite an increase in the white blood cell count, the leukaemic leukocytes are non-functional. The oral complications arising in leukaemic patients can be attributed to the direct and indirect effects of immunosuppressive chemotherapy. Methods:, This case report describes severe maxillary and mandibular necrotizing stomatitis and osteomyelitis in a young female patient after chemotherapy for acute leukaemia. On physical examination, the patient presented malnourished with pale skin, cervical lymphadenitis, frequent fever and generalized pain. The intra-oral clinical examination found halitosis, multiple ulcers, necrotizing stomatitis and osteomyelitis located in the maxillary and mandibular regions. The necrotizing stomatitis and osteomyelitis were treated locally with atraumatic removal of the necrotized tissues. The patient received a daily preventive protocol consisting of oral hygiene care, including twice daily brushing, and mouthrinses with a solution of chlorhexidine. She was also treated with systemic metronidazole and amoxicillin for 21 days. Results:, During the course of management the patient's oral condition improved with some re-epithelialization being noted. However, severe alveolar bone destruction remained evident. Thirty-two months after presentation of the initial symptoms, the patient died due to complications related to leukaemia recurrence (haemorrhage, sepsis and respiratory distress syndrome). Conclusions:, Dental monitoring during cancer treatment is imperative in order to emphasize the importance of dental plaque control and the maintenance of a healthy periodontal condition throughout medical treatment. [source] Osteoclast-targeting small molecules for the treatment of neoplastic bone metastasesCANCER SCIENCE, Issue 11 2009Makoto Kawatani Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical/biological approach for identifying osteoclast-targeting small molecular inhibitors. (Cancer Sci 2009) [source] Involvement of molecular mimicry between human T-cell leukemia virus type 1 gp46 and osteoprotegerin in induction of hypercalcemiaCANCER SCIENCE, Issue 3 2009Yasuko Sagara Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL), frequently associated with hypercalcemia and bone destruction. A positive correlation between the appearance of an antibody recognizing the central region (Asp197 to Leu216) on Gp46, gp46-197, and the severity of ATL has been demonstrated. In this study, five male Nihon Hakusyoku rabbits were immunized with a synthetic peptide corresponding to the gp46-197 region to clarify its action and mechanism. Two of the rabbits showed piloerection, anorexia, and somnolence, and died soon after booster administration. The serum calcium level of the dead rabbits was significantly high, compared to those of surviving rabbits. Interestingly, amino acid sequences homologous with gp46-197 were found in the carboxyl-terminal half of osteoprotegerin (OPG), an osteoclast inhibitory factor. To confirm the effect of the gp46-197 region on osteogenesis in vivo, the peptide was intraperitoneally administered to male Sprague-Dawley rats. The administration of the gp46-197 peptide resulted in a decrease of bone mineral density (BMD), a significant increase of serum calcium level, and inhibition of normal bone growth in both short- and long-term experiments. In rats, femoral growth inhibition by the gp46-197 peptide was restored by the coadministration of recombinant human OPG. Improvement by OPG in the adverse effect indicates that the central region of HTLV-1 Gp46 acts as an antagonist for OPG and leads to hypercalcemia. (Cancer Sci 2009; 100: 490,496) [source] Early colonization of non-submerged dental implants in patients with a history of advanced aggressive periodontitisCLINICAL ORAL IMPLANTS RESEARCH, Issue 1 2006Annemarie L. De Boever Abstract: The aim of the study was to evaluate the early colonization of non-submerged implants over a 6-month period in partially edentulous patients treated for advanced aggressive periodontal disease. In 22 patients treated for advanced aggressive periodontitis and in a supportive maintenance program for a period between 12 and 240 months at implant surgery, a total of 68 non-submerged dental implants were installed. Patients had a plaque score below 20%, and less than 20% of the pockets around the teeth were bleeding on probing (BOP). Using DNA-probes (micro-IDent®), the presence and concentration of five periodontal pathogens (Actinobacillus actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Tannerella forsythensis (Tf) and Treponema denticola (Td)) were determined in the five deepest pockets of the rest dentition pre-operatively and after 6 months as well as five places around each implant 10 days, 1 month, 3 months and 6 months after surgery. In each patient, a test to determine the genotype interleukin-1 (IL-1) was performed (PST , micro-IDent®). After 6 months, no difference in microbial composition as compared with baseline was found around the teeth in five patients, in 12 minute differences and in five patients important differences were observed. Ten days after surgery, three patients had a complete similar bacterial composition between teeth and implants. In 14 patients, the composition was fairly similar, while large differences in composition and concentration occurred in five patients. This microbiota around the implants remained almost unchanged over a 6-month period and did not hamper the clinical and radiographic osseointegration and did not lead to peri-implantitis, mucositis or initiation of bone destruction. [source] Implant osseointegration in the irradiated mandibleCLINICAL ORAL IMPLANTS RESEARCH, Issue 3 2002A comparative study in dogs with a microradiographic, histologic assessment Abstract: This research focuses on the effects of radiotherapy on the osseointegration of dental implants placed before or after radiotherapy in 11 male beagles. After the extraction of all mandibular premolars 1st and 2nd molars, three dogs were implanted without radiotherapy (Control group), four dogs were irradiated 4 weeks after implantation (IrA group) and four dogs were irradiated 8 weeks before implantation (IrB group). Eight implants were placed in each dog, in an alternating pattern: four nonsubmerged ITI Bonefit® titanium plasma spray-coated and four submerged Steri-Oss® hydroxyapatite-coated. The irradiated dogs received 4.3 Gy daily for 10 days. Two different fluorescent markers were administered at the time of implantation and of irradiation. The dogs were sacrificed 6 months after implantation, i.e. 5 months after radiotherapy for the IrA group and 8 months for the IrB group. Each mandible was submitted to histological and microradiographic analysis. Bone formation occurred around 85 of the 88 implants and consisted mostly of the successive deposit of woven and lamellar bone. Both irradiated groups showed obvious bone remodeling in alveolar bone as well as in the basilar part of the mandible. Nevertheless, in the IrA group, the resorption phenomena predominated over osteogenesis. The balance between these two opposite processes seemed to be restored 8 months after the end of radiotherapy (IrB group). In spite of focal lesions of radiation-specific bone destruction emphasized in some irradiated dogs, we conclude from our results that osseointegration of dental implants is possible in irradiated bone tissue. Résumé Cette recherche met en évidence les effets de la radiothérapie sur l'ostéointégration d'implants dentaires placés avant ou après une radiothérapie chez onze beagles mâles. Après l'extraction des prémolaires et des premières et secondes molaires à la mandibule, trois chiens ont été implantés sans être irradiés (groupe contrôle), quatre chiens ont été irradiés quatre semaines après l'implantation (groupe IrA) et quatre chiens ont été irradiés huit semaines avant l'implantation (groupe IrB). Huit implants ont été placés chez chaque chien, alternativement quatre implants ITI Bonefit® recouverts d'un plasma spray titane, placés suivant la technique enfouie et quatre implants Steri-Oss® recouverts d'hydroxyapatite et placés suivant la technique non-enfouie. Les chiens irradiés ont reçu une dose quotidienne de 4,3 Gy pendant dix jours. Deux marqueurs fluorescents de l'ostéogenèse ont été administrés, l'un au moment de l'implantation et l'autre au cours de l'irradiation. Les chiens ont été sacrifiés six mois après l'implantation, autrement dit, cinq mois après la radiothérapie pour le groupe IrA et huit mois après la radiothérapie pour le groupe IrB. Chaque hémimandibule a été soumise à une analyse histologique et microradiographique. De l'os néoformé a été mis en évidence autour de 85 implants sur les 88 placés. Cette formation osseuse est constituée d'os fibreux réticulé suivi d'une apposition d'os lamellaire. Les deux groupes irradiés ont montré un incontestable remaniement osseux non seulement au niveau de l'os alvéolaire mais aussi au niveau de la partie basilaire de la mandibule . Toutefois, dans le groupe IrA, les phénomènes de résorption osseuse dominent ceux de l'ostéogenèse. L'équilibre entre la résorption et l'apposition ossseuse semble être rétabli huit mois après la fin de la radiothérapie (groupe IrB). Malgré la présence de lésions osseuses, typiques de l'irradiation, relevées au niveau de certains chiens irradiés, nous concluons, d'après nos résultats que l'ostéointégration d'implants dentaires est possible dans le tissu osseux irradié. Zusammenfassung Diese Studie untersucht den Effekt der Radiotherapie auf die Osseointegration von dentalen Implantaten, welche vor oder nach Radiotherapie bei 11 männlichen Beagle-Hunden eingesetzt wurden. Im Unterkiefer wurden alle Prämolaren, die ersten und zweiten Molaren extrahiert. Bei 3 Hunden wurden die Implantate ohne Radiotherapie eingesetzt (Kontrollgruppe), bei 4 Hunden wurde 4 Wochen nach der Implantaten eine Bestrahlung durchgeführt (IrA Gruppe) und bei 4 Hunden wurde eine Bestrahlung 8 Wochen vor der Implantation durchgeführt (IrB Gruppe). Jedem Hund wurden 8 Implantate eingesetzt. Es wurden abwechselnd 4 transmukosale ITI Bonefit® Implantate mit Titanplasmabesichtung und 4 submukosale Steri-Oss® Implantate mit Hydroxyapatitbeschichtung eingesetzt. Die bestrahlten Hunde erhielten während 10 Tagen 4.3 Gy pro Tag. Zum Zeitpunkt der Implatation und der Bestrahlung wurden 2 verschiedene fluoreszierende Marker verabreicht. Die Hunde wurden 6 Monate nach der Implantation, d.h. 5 Monate nach Bestrahlung für die IrA Gruppe und 8 Monate nach Bestrahlung dür die IrB Gruppe, geopfert. Jeder Unterkiefer wurde histologisch und histomorphometrisch untersucht. Bei 85 der 88 Implantate trat eine Knochenbildung auf, welche zumeist aus einer successiven Ablagerung von Geflecht- und Lamellenknochen bestand. Beide bestrahlten Gruppen zeigten deutliche Knochenumbauvorgänge sowohl im Alveolarknochen als auch im basalen Teil des Unterkiefers. Jedoch waren in der IrA Gruppe die Resorptionsphänomene dominanter als die Osteogenese. Das Gleichgewicht zwischen diesen beiden entgegengesetzten Prozessen schien 8 Monate nach Beendigung der Radiotherapie (IrB Gruppe) wiederhergestellt. Obwohl einige lokale Läsionen von bestrahlungsbedingter Knochendestruktion bestanden, ziehen wir aufgrund unserer Resultate die Schlussfolgerung, dass eine Osseointegration von dentalen Implantaten im bestrahlten Knochen möglich ist. Resumen Esta investigación enfocada sobre los efectos de la radioterapia en la osteointegración de implantes dentales colocados antes o desqués de la radioterapia en 11 beagles machos. Tras la extracción de todos los premolares mandibulares, primeros y segundos molares, 3 perros fueron implantados sin radioterapia (Grupo de control), 4 perros fueron irradiados 4 semanas tras la implantación (Grupo IrA) y 4 perros se irradiaron ocho semanas antes de la implantación (Grupo IrB). Se colocaron 8 implantes en cada perro, con un patrón alternante: 4 ITI Bonefit® no sumergidos de titanio con cubierta pulverizada de plasma de titanio y 4 Steri-Oss® sumergidos cubertos de hidroxiapatita. Los perros irradiados recibieron 4,3 Gy diariamente durante 10 días. Se administraron dos diferentes marcadores fluorescentes en el momento de la implantación y de la irradiación. Los perros se sacrificaron 6 meses tras la implantación, esto es, 5 meses fras la radioterapia para el grupo IrA y 8 meses para el grupo IrB. Cada mandíbula fue sometida a análisis histológico y microradiográfico. La formación de hueso tuvo lugar alrededor de 85 de los 88 implantes y consistió mayoritariamente en depósitos sucesivos de hueso entretejido y lamelar. Ambos grupos irradiados mostraron un obvio remodelado óseo en el hueso alveolar al igual que en la parte basilar de la mandíbula. Sin embargo, en el grupo IrA, el fenómeno de reabsorción fue predominante en aquellos de osteogénesis. El equilibrio entre estos dos procesos contrarios pareció restaurarse a los 8 meses del final de la radioterapia (Grupo IrB). A pesar de las lesiones focales de destrucción ósea específica de la radiación enfatizada en algunos perros irradiados, concluimos de nuestros resultados que la osteointegración de implantes dentales es posible en tejido óseo irradiado. [source] | ||||||||||||||||||||||||||||