No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The Effect of Demineralized Dentin Matrix Graft alone and Combined with Statin and Propolis on Bone Repair. (A Histological Study)
ResearchGate has not been able to resolve any citations for this publication.
It has been reported that simvastatin, which is a cholesterol synthesis inhibitor and a therapeutic drug for hypercholesteremia, stimulates bone morphogenetic protein 2 expression in osteoblasts, suggesting potentiality of simvastatin in local bone augmentation. We prepared bovine atelo-collagen or calcium sulfate containing simvastatin and applied these materials to the rat lower incisor sockets. After 4 weeks, the bone of the extracted site was examined radiographically and histologically. Calcium sulfate containing simvastatin remarkably increased the thickness of the alveolar bone. This effect was not observed when simvastatin alone was applied or when atelo-collagen was used as a drug carrier. Although further studies are required, the present results indicate that simvastatin augments bone around tooth socket, which is carrier-dependent.
Osteoporosis is a major health problem affecting both men and women. Statins, besides their action as lipid-lowering agents, seem to have additional pleiotropic properties, among them a beneficial effect on bone mineral density. The entirety of experimental and the majority of clinical studies as well as the only relevant meta-analysis suggest that statins have an anabolic effect on bone metabolism. Statins, osteoporosis and adipogenesis share the same pathway, RANKL/OPG. It would appear that an imbalance in this pathway could be responsible for the manifestation of some metabolic disorders such as diabetes mellitus, atherogenesis, multiple myeloma, osteoporosis. Possibly in the future, drugs which can intervene in this biochemical and pathophysiological cascade, like statins, in a variety of doses, could be used for the management of ectopic ossification syndromes and other bone disorders, even as an additive treatment. Until then, further large longitudinal randomized controlled studies for each statin separately are required to confirm this hypothesis.
The aim of this study was to evaluate histomorphometrically the effect of alveolex (Propolis 10%) on the repair of bone cavities in the calvaria of rats.
A 5 mm diameter bone defect was made in the calvaria of male Wistar rats using the drill-type trephine. The defects were filled with rhBMP-2+Alveolex, rhBMP-2, Alveolex, or coagulum. Twenty-eight animals with seven subjects on each were sacrificed 30 days after surgery and samples were fixed and embedded in paraffin. Histological sections stained by HE (hematoxylin and eosin) were obtained from the calvaria bone defect and analyzed by a differential point-counting method.
Group I and II, rhBMP-2+Alveolex and rhBMP-2, respectively, presented higher levels of newly formed bone than other groups (P < 0.001). There were not significant differences between groups I and II (P > 0.05). In addition, there was not significant difference between groups III and IV, Control-Coagulum and Alveolex, respectively (P > 0.05).
Alveolex has increased the bone repair in calvaria defects of rats when associated to rhBMP-2, however without significant differences for rhBMP-2 isolated group; Alveolex isolated group showed the lowest levels of newly formed bone with no significant differences to coagulum group (control).
Vascular endothelial growth factor (VEGF) is a key regulator of pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. Bee products [royal jelly (RJ), bee pollen, and Chinese red propolis] from the honeybee, Apis mellifera, have been used as traditional health foods for centuries. The aim of this study was to investigate the anti-angiogenic effects of bee products using human umbilical vein endothelial cells (HUVECs).
In an in vitro tube formation assay, HUVECs and fibroblast cells were incubated for 14 days with VEGF and various concentrations of bee products [RJ, ethanol extract of bee pollen, ethanol extract of Chinese red propolis and its constituent, caffeic acid phenethyl ester (CAPE)]. To clarify the mechanism of in vitro angiogenesis, HUVEC proliferation and migration were induced by VEGF with or without various concentrations of RJ, bee pollen, Chinese red propolis, and CAPE.
RJ, bee pollen, Chinese red propolis, and CAPE significantly suppressed VEGF-induced in vitro tube formation in the descending order: CAPE > Chinese red propolis > bee pollen > RJ. RJ and Chinese red propolis suppressed both VEGF-induced HUVEC proliferation and migration. In contrast, bee pollen and CAPE suppressed only the proliferation.
Among the bee products, Chinese red propolis and CAPE in particular showed strong suppressive effects against VEGF-induced angiogenesis. These findings indicate that Chinese red propolis and CAPE may have potential as preventive and therapeutic agents against angiogenesis-related human diseases.
Xenogeneic transplants of powdered, dehydrated, demineralized matrix of bone and tooth were well tolerated in three species of rodents. Differences between the species were found in competence of fibroblasts to be transformed into cartilage and bone in vivo by these preparations. Rat fibroblasts were most susceptible to transformation of this sort; they were transformed by demineralized dentin of guinea pig, mouse, and rat, and to a limited extent, by a specimen of decalcified human bone.
Understanding of the human musculoskeletal system and common clinical disorders of bones, joints and soft tissues has been enhanced by the use of experimental animal models. Articles reporting on the results of these biomedical experiments frequently include conclusions that are based on the assumption that the biology of the animal model is similar to that of a human being for the disease process under investigation. The purpose of this investigation was to study the criteria and the considerations for selection of an animal model in musculoskeletal research. Selected journals from the musculoskeletal literature published between January 1991 and November 1995 were scrutinized for the use of animal models, and several criteria used in the selection of the various animal models were investigated. The selection criteria analyzed in this study included the biologic characteristics of the model, budget issues, the reproducibility of a musculoskeletal disease, and animal handling factors. A computer-assisted search of the musculoskeletal literature published from 1965 to 1995 was also performed to screen for reports comparing mammals used as animal models in terms of these selection criteria. Our findings imply that the selection of animal models in research of the musculoskeletal system is based partly on non-standardized criteria that are not necessarily based on the biology of the disease process being studied. In addition, there are limited comparative data on the selection and use of different animals for musculoskeletal research. We believe the selection of models should be more standardized based on both biological and non-biological criteria. Researchers would then be able to put in a more meaningful perspective the results of research using animal models and their clinical implications.
The aim of this work was to evaluate the effectiveness of homogenous demineralized dentin matrix (HDDM) slices in surgical bone defects created in the mandibles of rabbits and occluded with a polytetrafluoroethylene (PTFE) membrane in the promotion of bone growth.
Surgical bone defects were created in 36 adult rabbits and divided into 4 groups: bone defect (control), bone defect with PTFE membrane, bone defect with HDDM, and bone defect with both HDDM and a PTFE membrane (HDDM + PTFE). The rabbits were sacrificed after 30, 60, and 90 days, and the bone defects were examined histologically and by histomorphometric analysis (analysis of variance and the Tukey test).
The volume of newly formed bone matrix was significantly greater in the HDDM and HDDM + PTFE groups than in the control and PTFE groups. The discrete inflammatory reaction found in the HDDM and HDDM + PTFE groups did not prevent the osteopromotive activity of the dentin matrix.
HDDM slices were biocompatible and were resorbed during the bone remodeling process. They stimulated the newly formed bone until 30 days after implantation.
Bone repair was accelerated in the bone defects treated with HDDM in comparison to the control group.
Bone development occurs by two mechanisms: intramembranous bone formation and endochondral bone formation. Bone tissue forms by eventual differentiation of osteoprogenitor cells into either mesenchymal osteoblasts (MOBL), which synthesize woven bone in random orientation, or surface osteoblasts (SOBL), which synthesize bone on surfaces in a well oriented lamellar array. Bone repair uses the same formation patterns as bone development but the specific mechanism of repair is determined by the biomechanical environment provided. Bone synthesis and maintenance are highly dependent on the blood supply of bone and on cell-cell communication via the lacunar-canalicular system. Recent investigations highlight the molecular cascades leading to cell differentiation, the components of the structural proteins such as the various collagens, and tissue vascularization. The patterning of bone matrix from an initial woven to an eventual lamellar orientation is essential for bone to develop its maximum strength. This review demonstrates the repetitive nature of woven to lamellar bone formation as mediated by MOBLs and SOBLs in both normal vertebrate bones and bone repair. Repair, using endochondral, primary, direct and distraction osteogenesis mechanisms, is reviewed along with the associated molecular, vascular, and biophysical features.
Propolis collected by honeybees from various plant sources is a resinous hive product possessing a broad spectrum of biologic activities. Propolis has been used extensively in the diet to improve health and prevent disease. The purpose of this study was to analyze the morphometric and histopathologic changes associated with experimental periodontitis in rats in response to the systemic administration of propolis.
Forty Wistar rats were divided into four experimental groups: non-ligated (NL; N = 10); ligature only (LO; N = 10); and systemic administration of ligature and propolis (100 mg/kg body weight per day [Pro100; N = 10] or 200 mg/kg body weight per day [Pro200; N = 10]). Silk ligatures were placed at the gingival margin of the lower first molars in both mandibular quadrants. The study duration was 11 days, and the animals were sacrificed at the end of this period. Changes in alveolar bone levels were clinically measured, and tissues were histopathologically examined to assess the differences among the study groups.
At the end of 11 days, alveolar bone loss was significantly higher in the LO group compared to the NL, Pro100, and Pro200 groups (P <0.05). Osteoclast numbers in the LO group were significantly higher than those of the NL, Pro100, and Pro200 groups (P <0.05). Both dosages of propolis significantly reduced the periodontitis-related bone loss, but the differences between the two propolis groups were not statistically significant (P >0.05).
The findings of this study provide morphologic and histologic evidence that propolis, when administered systemically, prevents alveolar bone loss in the rat model.
Statins are known for their beneficial effects on cardiovascular diseases. Besides the lipid-lowering properties, statins exert their anabolic effects on bone by differentiating mesenchymal cells to osteoblasts via upregulating BMP-2 and protecting osteoblasts from apoptosis. In addition, statins have been suggested to be anti-osteoclastic by reducing the osteoclast differentiation and activity. Several in vivo and clinical studies have confirmed the beneficial effects of statins in treatment of osteoporosis and fracture injuries. However, controversial results exist showing statins may have no benefit and in some instances, they may retard bone repair. Different factors such as type, rout of administration, dose and dosage of statins, and the injury model seem to be involved for such controversies. In the present study, the most important issues regarding statins have been reviewed to find out how statins may be beneficial and statin therapy can be improved for treating the osteoporosis and fracture injuries. The lipophilic statins particularly Simvastatin and Atorvastatin are the most investigated statins with beneficial results on bone healing and turnover. Most of the in vivo and clinical studies performed systemic route of administration for treating osteoporosis, with much higher clinical doses than the lipid lowering therapy, which increases the statin related side and out of target effects. In contrast, most of the in vivo studies that used statins for fracture repair, have applied local delivery methods with much lower doses via tissue engineering approaches. However, local delivery of statins and statin therapy for fracture repair both have low application in the clinical setting and such methods are still under in vivo investigation. Future clinical trials are needed to elucidate how delivery systems and tissue engineering technologies are able to improve the outcome of statin therapy.
Copyright © 2015. Published by Elsevier B.V.
The discovery that statins had bone anabolic properties initiated many investigations into their use for treatment of bone catabolic diseases, such as osteoporosis. This paper reviews the molecular basis of statin's role in bone metabolism, and animal and human studies on the impact of systemic statins on osteoporosis-induced bone fracture incidence and healing, and on bone density. Limitations of systemic statins are described along with alternative dosing strategies, including local applications and bone-targeting systemic preparations. The principal findings of this review are: 1) traditional oral dosing with statins results in minimal efficacy in the treatment of osteoporosis; 2) local applications of statins show promise in the treatment of accessible bony defects, such as periodontitis; and 3) systemically-administered statins which can target bone or inflammation near bone may be the safest and most effective strategy in the treatment of osseous deficiencies.
Tissue engineering techniques have been proven effective in bone regeneration and repairing load-bearing bone defects. Previous
studies, however, have heretofore been limited to the use of slowdegradable or natural biomaterials as scaffolds. There are,
however, no reports on using biodegradable, synthetic beta-tricalcium phosphate (β-TCP) as scaffolds to repair weight-bearing
bone defects in large animals. In the present study, highly porous β-TCP scaffolds prepared by the polymeric sponge method
were used to repair goat tibial defects. Fifteen goats were randomly assigned to one of three groups, and a 26 mm-long defect
at the middle part of the right tibia in each goat was created. In Group A (six goats), a porous β-TCP ceramic cylinder that
had been loaded with osteogenically induced autologous bone marrow stromal cells (BMSCs) was implanted in the defect of each
animal. In Group B (six goats), the same β-TCP ceramic cylinder without any cells loaded was placed in the defect. In Group
C (three goats), the defect was left untreated. In Group A, bony union can be observed by gross view, X-ray and micro-computed
tomography (Micro-CT) detection, and histological observation at 32 weeks post-implantation. The implanted β-TCP scaffolds
were almost completely replaced by tissue-engineered bone. Bone mineral density in the repaired area of Group A was significantly
higher (p 0.05). In Group C, little or no new bone was formed, and non-union occurred, showing that the 26 mm segmental defect of
the goat tibia was critical sized at 32 weeks. Thus, it can be concluded that the mechanical properties of the BMSCs/β-TCP
composites could be much improved via tissue engineering approach and β-TCP might be used to repair the weight-bearing segmental
defects of goat tibias.
There is a great trend to use natural materials as a cure for many diseases. Alternative medicine has made a lot of contributions to modern medical practice. Propolis is a Greek word meaning "defender of the city". It is the glue that honey bees use to seal their hives. Propolis has a strong historical background. It has been used in different cultures and civilizations. Propolis has anti-bacterial, anti-viral and anti-fungal effects. Its anti-cancer effect has also been observed. Propolis has also been used in dentistry for surgical wound healing, rool canal treatment, pulp capping and tooth hypersensitivity. Different commercial propoiis products are available in market. Propolis has a promising role in future medicine. Further research is needed in its application in clinical dentistry.
The cholesterol-lowering drug, simvastatin, is a pro-drug of a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and inhibits cholesterol synthesis in humans and animals. In addition, the bone effects of statins including simvastatin are being studied. We assessed the effects of simvastatin on osteoblastic differentiation in nontransformed osteoblastic cells (MC3T3-E1) and rat bone marrow cells. Simvastatin enhanced alkaline phosphatase (ALP) activity and mineralization in a dose- and time-dependent fashion. This stimulatory effect of the statin was observed at relatively low doses (significant at 10−8 M and maximal at 10−7 M). Northern blot analysis showed that the statin (10−7 M) increased in bone morphogenetic protein-2 as well as ALP mRNA concentrations in MC3T3-E1 cells. Simvastatin (10−7 M) slightly increased in type I collagen mRNA abundance throughout the culture period, whereas it markedly inhibited the gene expression of collagenase-1 between days 14 and 22 of culture. These results indicate that simvastatin has anabolic effects on bone through the promotion of osteoblastic differentiation, suggesting that it could be used for the treatment of common metabolic bone diseases such as osteoporosis.
To clarify the mechanism of the stimulatory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on bone formation, we investigated the effect of pitavastatin, a newly developed statin, on expression of bone morphogenetic protein-2 (BMP-2) and osteocalcin in primary cultured human osteoblasts. Pitavastatin increased the expression level of mRNA for BMP-2, and much more effectively for osteocalcin. This stimulatory effect was abolished by the addition of geranylgeranyl pyrophosphate, an essential molecule for prenylation of small GTP-binding proteins such as Rho GTPase, but not by inhibitors of nitric oxide synthase and various protein kinases. Pitavastatin suppressed the Rho-associated kinase (Rho-kinase) activity. Hydroxyfasudil, a specific inhibitor of Rho-kinase, increased BMP-2 and osteocalcin expression. These mRNA levels were strongly suppressed by dexamethasone, but restored by co-treatment with hydroxyfasudil. These observations suggest that the Rho-kinase negatively regulates bone formation and the inhibition of Rho and Rho-kinase pathway is the major mechanism of the statin effect on bone. Moreover, a Rho-kinase inhibitor may be a new therapeutic reagent for the treatment of osteoporosis such as glucocorticoid-induced osteoporosis.
In this study we investigated the possible use of human demineralised dentine matrix (DHDM), obtained from the extracted teeth, as bone graft material and evaluated the expression of vascular endothelial growth factor (VEGF) induced by this material in the healing process of tooth sockets of rats.
To evaluate bone regeneration and expression of VEGF induced by DHDM, thirty-two male Wistar rats weighing approximately 200 g were used. After maxillary second molar extraction, the left sockets were filled with DHDM and the right sockets were naturally filled by blood clot (control). The animals were sacrificed at 3, 7, 14 and 21 days after surgery and upper maxillaries were processed for histological, morphometric and immunohistochemical analyses. DHDM was used to evaluate the mechanical effect of bone graft material into sockets. Expression of VEGF was determined by immunohistochemistry in all groups.
Our results demonstrated a significant increase in the newly formed bone tissue in sockets of 7, 14 and 21 days and a significant increase in VEGF expression at days 7 and 14 on treated sockets.
Our results showed that DHDM increases the expression of VEGF and accelerates the healing process in rats tooth sockets, by stimulating bone deposition and also vessels formation. These results suggest that DHDM has osteoinductive/osteoconductive potential and may represent an efficient grafting material on guided bone regeneration.
Propolis is a substance of honeybee origin with known antioxidant effects. The purpose of this study was to examine the effects of propolis on fracture healing and the antioxidant system in an experimental setting. Thirty-two rats that underwent experimental femur fracture and then fixation were randomly allocated in one of four groups: two control groups (Control-3w and Control-6w) and two treatment groups (Propolis-3w and Propolis-6w). Treatment groups received propolis until killing (at 3 or 6 weeks). X-ray, histological, bone mineral density measurement findings and endogenous antioxidant levels were examined. The bone mineral density was higher, radiological and histological evaluation scores were better, and superoxide dismutase, total glutathione and myeloperoxidase levels were lower among the rats that received oral propolis treatment compared with the controls. In addition, bone mineral density and histological assessment scores showed time-dependent improvement in the treatment group. In conclusion, the findings of this study suggest that propolis has some time-dependent beneficial effects on fracture healing.
The effectiveness of honey as a therapeutic agent has been unequivocally demonstrated in the literature reviewed in Part 1 of this article published in 1999, but the biochemical explanation of these effects is more hypothetical. However, a rational explanation can be seen when one looks at the scientific literature outside that on honey. Some of the components of honey are substances known to have physiological actions that would explain many of its therapeutic effects. In addition, research on honey has shown directly that it has physiological actions that would give therapeutic effects. This is the published version of an article published in the journal: New Zealand BeeKeeper. Used with permission.
Articular cartilage repair remains a major obstacle in tissue engineering. In the present study, we investigated the potential for demineralized dentin matrix (DDM; organic material derived from dentin) obtained from extracted teeth to be used as bone graft material. To evaluate the extent to which DDM induces osteochondral regeneration, we implanted DDM from bovine teeth in rabbit knees with full-thickness articular cartilage defects. Thirty-three 13-week-old male rabbits weighing 2.5-3.0 kg were randomly assigned to a control group (n = 11) and two experimental groups (n = 11 for each group). The knees were divided into three groups according to the subsequent treatment: in group I (n = 22), the control group, the defect was left untreated; and in groups II (n = 22) and III (n = 22), 50 and 100 mg of DDM, respectively, was implanted. The rabbits were killed 1, 3, 6, or 9 weeks after the surgical procedure, and the knees were collected. The harvested tissues were examined radiographically and histologically. The 100-mg DDM group (group III) had significantly more new bone forming inside the defect (as measured using the BV/TV value) compared with the other two groups as early as at week 3 postoperatively, but thereafter, the difference gradually decreased. Cartilage repair in the surface region remained significantly better in group III because hyaline-like cartilage appeared in the peripheral area of the defect at week 6 and the surface was covered with hyaline-like cartilage with a thickness similar to that of normal cartilage at week 9. In conclusion, the results of this study suggest that DDM acts as a scaffold for osteochondral regeneration, yielding active new bone formation early in the postoperative period. Thus, DDM may represent an effective bone implant material.
The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis were started from 1971. The first potent inhibitor, ML-236B (compactin), was found from the culture broth of Penicillium citrinum. Among many derivatives of ML-236B, pravastatin sodium (hereafter refer to pravastatin) was finally selected because of its potency and tissue selectivity. Since pravastatin has a hydroxyl group at 6 beta position in the skeleton of decaline of ML-236B, the microbial hydroxylation was adopted for the production of pravastatin. Streptomyces carbophilus was finally chosen as a potent converter with the formation of a lesser amount of by-products. For the sake of industrial production of pravastatin, many devices and improvements were performed for selecting high potent strains and for culturing conditions both with ML-236B and pravastatin. Pravastatin strongly inhibited the sterol synthesis in freshly isolated rat hepatocytes, but only weakly inhibited in the cells from nonhepatic tissues. This selective inhibition of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments by using rats and mice. Pravastatin markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. Pravastatin showed the preventive effect on the development of coronary atherosclerosis and xanthoma in young WHHL rabbits in consequence of maintaining the serum cholesterol levels low. In the clinical trials, pravastatin significantly reduced serum cholesterol and low density lipoprotein cholesterol levels, whereas inversely increased high density lipoprotein cholesterol levels.
Simvastatin (epistatin; synvinolin; MK 733), an HMG-CoA reductase inhibitor, acts by decreasing cholesterol synthesis and by increasing low density lipoprotein (LDL) catabolism via increased LDL receptor activity. In patients with heterozygous familial and nonfamilial hypercholesterolaemia, orally administered simvastatin 10 to 40mg once daily reduces plasma total and LDL-cholesterol concentrations by about 30 to 45%. It also produces a beneficial moderate decrease in plasma triglycerides and a small, although significant, increase in high density lipoprotein (HDL)-cholesterol. Like many other hypocholesterolaemic agents simvastatin does not appear useful in patients with homozygous familial hypercholesterolaemia who lack LDL receptors. The hypocholesterolaemic activity of simvastatin is greater than that of the bile acid sequestrants, probucol and the fibrates. Combined administration of simvastatin with bile acid sequestrants results in further reductions in plasma cholesterol levels beyond those seen with either drug alone. Simvastatin appears well tolerated in the short to medium term, but its long term tolerability needs to be confirmed. No comparisons of simvastatin and other HMG-CoA reductase inhibitors have been reported. As yet there have been few investigations to determine the impact of simvastatin or other HMG-CoA reductase inhibitors on cardiovascular events relative to their hypocholesterolaemic effects, but at least one such trial is ongoing. Simvastatin, like other HMG-CoA reductase inhibitors, has considerable potential advantages over other classes of hypocholesterolaemic agents, i.e. the magnitude of its cholesterol-lowering effect and convenience of administration. If further study confirms long term tolerability and an impact on cardiac mortality and morbidity, then simvastatin and others of its class should offer a significant new approach to the treatment of hypercholesterolaemia.
Bone morphogenetic protein (BMP) was extracted from bone matrix, dentin matrix, and wound tissue after tooth extraction in rabbits, and purified. These purified fractions were shown to be homogeneous by sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis (SDS-PAGE), and induced new bone in situ in 3 weeks when implanted into the calf muscles of Wistar rats. The dentin matrix-derived BMP was different from the other two types in molecular weight and the properties revealed in the process of purification. However, each tissue-derived BMP was shown to induce new bone growth in a bioassay of xenogenic implantation. For this reason, BMP is thought to have subunits with certain commonalities in different tissue.
The purpose of this study was to examine histologically the effects of propolis topical application to dental sockets and skin wounds. After topical application of either a 10% hydro-alcoholic solution of propolis or 10% hydro-alcoholic solution alone, cutaneous wound healing and the socket wound after tooth extraction were examined. The rats were sacrificed at 3, 6, 9, 15 and 21 days after the operation. The specimens were subjected to routine laboratory studies after staining with hematoxylin and eosin. It was concluded that topical application of propolis hydro-alcoholic solution accelerated epithelial repair after tooth extraction but had no effect on socket wound healing.
Lovastatin is the first of a new class of cholesterol lowering drugs that competitively inhibit HMG-CoA reductase. This new drug decreases cholesterol synthesis and apolipoprotein B concentrations, and increases LDL receptor activity without adverse effects on other products in the cholesterol pathway. In patients with heterozygous familial or polygenic (non-familial) hypercholesterolaemia, oral lovastatin 20 to 40 mg twice daily reduces plasma total cholesterol and LDL-cholesterol concentrations by 25 to 40% over a period of several weeks. Lovastatin also produces decreases in plasma triglyceride and VLDL-cholesterol concentrations, although to a lesser extent. In addition, small though significant increases in HDL-cholesterol concentrations have been observed. Combined administration of lovastatin with other lipid-lowering drugs results in further reductions in plasma total and LDL-cholesterol concentrations beyond those seen with either drug alone. From findings in short term studies, lovastatin appears to be well tolerated with a low incidence of side effects. However, liver function tests and eye examinations for possible lens opacities are advised, and further long term studies in larger groups of patients are necessary before the side effect profile of lovastatin will be clearly established. As would be expected at this relatively early stage of its clinical 'life,' lovastatin has not yet been studied in a manner that would determine its effect on cardiovascular mortality during long term administration. Nevertheless, if the substantial improvements to patients' lipid and lipoprotein profiles observed in short term studies are maintained during long term administration, then lovastatin will have an important role in the pharmacological management of hyperlipidaemia.
. Fifty autogenous, 120 allogenic and 40 xenogenic demineralized dentin specimens as-well as 36 undemineralized allogenic specimens were implanted in the abdominal muscles of 74 male guinea pigs for periods ranging from 4 to 12 weeks. An experimental model for the first and second set reaction in allogenic ear skin grafts was established in 10 male guinea pigs. The mean survival times of the first and second sets of these grafts were 10.1 days, s.d. = 1.57 and 5.2 days, s.d. = 0.78, respectively. Repeated implantation of both undemineralized, and demineralized and lyophilized allogenic dentin evoked an immune response in the host resulting in an accelerated skin graft rejection. Furthermore, in the second and third sets of implants the bone inducing process was either prevented (undemineralized dentin) or reduced (demineralized and lyophilized dentin). Xenogenic demineralized dentin failed to induce osteogenesis, probably due to an intense host immune response. The first set of allogenic demineralized dentin implants, on the other hand, induced bone formation in a high percentage of cases, it even gave the impression of enhancing the induction process compared to autogenous dentin.
EXPERIMENTS by Charles B. Huggins and his associates,1 and many others during the past thirty years,2-11 demonstrate that whole toothbuds and parts of toothbuds possess the capacity to grow and develop in areas of the body other than the jawbone, even in the form of explants in tissue culture. The toothbud not only continues its characteristic development, but also exhibits the capacity to induce undifferentiated connective tissues to form bone. To explain these observations, Hoffman12 postulates that the enamel organ and its derivative, Hertwig's epithelial root sheath, stimulates connective tissue cells to differentiate into bone cells, while Zussman13 contends that odontoblasts which had previously participated in dentin formation can produce bone even when not in contact with oral tissues. Except that the new bone originates from proliferating living cells in both the transplanted tooth and in the host bed, present knowledge of the local physiology of
The fate of implants of decalcified dentine was compared with that of decalcified bone, tendon and muscle in three different sites: muscle pouch, drill-hole in mandible, and extracted tooth socket. Within the implants of dentine and bone matrix in areas undergoing resorption by collagenolytic mesenchymal cells and sprouting capillaries, a consistently reproducible induction system was set up for osteogenesis. Similarly prepared tendon and muscle implants did not induce osteogenesis. Except that the new bone developed from the interaction of hypertrophied mesenchymal cells with extracellular substances in the matrix of dentine and bone, and that a film of cement substance generally separates the old and new tissue, the local physical-chemical reactions are obscure. Transfer of 3H-glycine does not appear to occur locally between the old dentine matrix and ingrowing new cells of the host.
Hypercholesterolemia, particularly an elevated level of low-density lipoprotein (LDL) cholesterol, is an unarguably established risk factor for coronary artery disease (CAD). It is equally well established that lowering LDL cholesterol levels will decrease CAD-related morbidity and mortality in patients with established CAD. Although lipid-lowering therapy is known to retard the progression of atherosclerosis in patients with native coronary arteries, its effect in patients with coronary bypass grafts, which are particularly vulnerable to occlusion, is less well understood. Moreover, whereas several major clinical trials have documented the benefits of lowering LDL cholesterol in a variety of patient subpopulations, there has been far less clarity surrounding the question of whether aggressive lowering of LDL cholesterol is of greater benefit than moderate lowering of LDL cholesterol. The Post Coronary Artery Bypass Graft (Post-CABG) trial, a multicenter, randomized, double-blind clinical trial comprising 1,351 patients with elevated levels of LDL cholesterol and a history of bypass surgery was designed to determine whether aggressive lowering of LDL cholesterol levels with therapy based on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") is more effective than moderate lowering in delaying the progression of atherosclerosis in bypass grafts. Quantitative computer-assisted angiography was conducted at baseline and again at an average of 4.3 years. The primary angiographic outcome was the mean percentage per patient of grafts with a decrease of > or = 0.6 mm in lumen diameter. Patients who received aggressive therapy were significantly more likely than their moderate-treatment counterparts to achieve and maintain LDL cholesterol levels within the National Cholesterol Education Program's (NCEP's) recommended target of < or = 100 mg/dL (< or = 2.59 mmol/L). Moreover, the mean percentage of grafts with progression of atherosclerosis was 27% for aggressively treated patients, compared with 39% for those who were randomized to the moderate-treatment group (p < 0.001). This study demonstrates that aggressive lipid lowering is practical and worthwhile in at-risk patients. Aggressive treatment is far more effective than moderate treatment in lowering LDL cholesterol levels to the NCEP target level of < or = 100 mg/dL (< or = 2.59 mmol/L), and this intervention decreases the progression of atherosclerosis.
The purpose of this study was to investigate whether bone fracture properties change with species (humans, baboon, canine, bovine, and rabbit). A single-layer compact sandwich (SCS) specimen and fractography were employed to evaluate bone fracture properties. In conjunction with measurements of the density and volume fractions of the mineral and organic phases, bone microstructure were also investigated. The results of this study indicate that bone fracture properties vary considerably with species. These differences are most likely due to variations in microstructural and compositional properties of bone (mineral and collagen) between the species. Baboon bone exhibited most similar fracture, microstructural, and compositional properties compared to humans. However, significant differences were found in bone fracture properties between humans and the other three animal species. These differences were reflected either in bone microstructures or compositional properties. This interspecies comparison facilitates a better understanding of animal models and suitable use of the animal models in future bone fracture studies.
Bone defects are often created in order to repair bone pathologies. In the aging population, the healing of such defects is very limited. Bone healing in aging depends on the availability of various hormone and growth factors. The ability of growth factors to enhance bone formation in femoral defects in old rats was tested. Bone defects were induced in femurs of old rats. A single dose of transforming growth factor-beta (TGF-beta), IGF-1, TGF-beta+IGF-1 or saline was inserted in the defect and bones were tested after 2 and 4 weeks. Radiology revealed that mineralization appeared in the 2 weeks group in defects treated with TGF-beta and in defects treated with TGF-beta, TGF-beta+IGF-1 in the 4 weeks groups. Computerized tomography (CT) coronal and axial images revealed that 4 weeks after treatment with TGF-beta+IGF-1, a complete bone bridge was observed. Morphology revealed that these defects were filled with trabecular bone. A less pronounced bone healing was observed after TGF-beta or IGF-1, while control specimens revealed partial healing of the bone defect. Biomechanical tests indicated that treatment with TGF-beta, IGF-1 or TGF-beta+IGF-1 resulted in a significant increase of bone bending rigidity compared to control in the 4 weeks group and that TGF-beta+IGF-1 was the most inductive in this respect. The ability to induce bone healing in aging by TGF-beta+IGF-1 is of a great clinical importance for restoration of bone strength and biomechanical properties of bone defects in aging.
Brazilian propolis has been classified into 12 groups based on physicochemical characteristics: five in the southern Brazil group (group 3), one in the southeastern Brazil group (group 12), and six in the northeastern Brazil group (group 6). The plant origins of these groups were investigated using reversed-phase high-performance thin-layer chromatography (RPHPTLC), reversed-phase high-performance liquid chromatography (RPHPLC), and gas chromatography-mass spectrometry (GC-MS). It was concluded that the origins of propolis group 3, group 6, and group 12 are resins of the poplar tree, Hyptis divaricata, and Baccharis dracunculifolia, respectively.
This work evaluated the osteoconductive properties of autogenous demineralized dentin matrix (ADDM) on surgical bone defects in the parietal bone of rabbits, using the guided bone regeneration technique and polytetrafluoroethylene (PTFE) membrane.
Surgical bone defects were created in 24 adult rabbits and repaired with either ADDM and PTFE (experimental group) or PTFE alone (control group). The ADDM had been obtained from the central incisors of the experimental rabbits. The rabbits were sacrificed after 15, 30, 60, and 90 days and the defects examined radiographically and histologically.
Radiographically, the defects in the experimental animals achieved radiopacity more quickly than the defects in the control group.
After 15, 30, 60, and 90 days of observation following surgery, the ADDM slices appeared to stimulate new bone formation. The dentin slices were completely incorporated into the new bone tissue and were resorbed during the bone repair.
Bone repair was accelerated on the bone defects treated with ADDM when compared to the control group.
The cholesterol-lowering drug simvastatin has been shown to stimulate murine calvarial bone growth after multiple injections. The purpose of this study was to test if similar bone stimulation could be induced by 2 single-dose drug delivery systems appropriate to periodontal therapy.
ICR Swiss mice were treated with the following protocols: 1) injection of methylcellulose gel alone, subcutaneously over the calvarium (INJ-GEL; n = 8); 2) injection of gel with simvastatin (INJ-SIM; 2.2 mg, n = 16); 3) polylactide membrane (PLA) containing gel alone implanted over calvarium (MEM-GEL; n = 10); 4) implanted PLA membrane containing gel and simvastatin (MEM-SIM; n = 10); and 5) untreated mice (n = 12). Animals were sacrificed after 22 or 44 days, calvaria decalcified and stained with hematoxylin and eosin, and images digitized and measured for bone thickness and area. Data were compared using analysis of variance.
INJ-SIM stimulated a 53% (P = 0.02) increase at the thickest point of calvarial bone, while MEM-SIM caused a highly significant (P < or = 0.0005) increase in bone thickness (159% to 172%) and bone area (144% to 180%) compared to gel controls. Simvastatin gels caused soft tissue inflammation, which appeared to be related to bone increases. If INJ-SIM animals showing leakage of gel and/or no inflammation were excluded from analysis, INJ-SIM resulted in more bone (58% to 83%) than gel controls. An insignificant amount of SIM-stimulated bone was lost over the long term (44 days).
A single, high dose of simvastatin gel can stimulate murine cranial bone apposition, particularly when delivered under an occlusive membrane. Both approaches should be investigated further for possible development for periodontal therapy.
Efeito da matriz dentina´riadentina´ria humana no reparo alveolar de ratos: avaliac¸a˜o histolo´gicahistolo´gica e imunohistoquı´mica
- J Almeida
- J Alves
Almeida J, Alves J. Efeito da matriz dentina´riadentina´ria humana
no reparo alveolar de ratos: avaliac¸a˜o histolo´gicahistolo´gica e
imunohistoquı´mica. RGO. 2007, 2:133-38.
Stimulation of bone formation in vitro and in rodents by statins
- G Mundy
- R Garrett
- S Harris
- J Chan
- D Chen
Mundy G, Garrett R, Harris S, Chan J, Chen D, et al.
Stimulation of bone formation in vitro and in rodents by
statins. Sci. 1999, 286:1946-49.
HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway
HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin
Invest. 2001, 108: 391-97.
Embryology, anatomy, and microstructure of bone, in Disorders of Bone and Mineral Metabolism
- R Recker
Recker R. Embryology, anatomy, and microstructure of
bone, in Disorders of Bone and Mineral Metabolism. New
York: Raven, 1992, pp 219-40.