Experimental development of bisphosphonate-related osteonecrosis of the jaws in rodents

Osteonecrosis of the jaw (ONJ) following the use of bisphosphonates has become of increased interest in the scientific community, due in particular to its as-yet-unsolved pathogenesis. An experimental model of ONJ was induced in normal male rats [alendronate (ALN); 1 mg/Kg/day; n = 10] and matched controls (saline solution; n = 10). After 60 days of drug treatment, all animals were subjected to extractions of the left first lower molars and were euthanized at 3 and 28 days postsurgery. The following analyses were performed: (i) descriptive and quantitative (scores) histological evaluation, (ii) stereometry of distal sockets and (iii) biochemical measurement of C-telopeptide cross-linked collagen type I (CTX) and bone-specific alkaline phosphatase (BALP). The results showed that 28 days postsurgery the animals treated with ALN had areas of exposed and necrotic bone, associated with significant infection, especially in the interalveolar septum area and crestal regions, compared with controls. The levels of CTX, BALP and bone volume, as well as the degrees of inflammation and vascularization, were significantly reduced in these animals. Therefore, analysis of the data presented suggests that ALN therapy is associated with the development of osteonecrosis in the jaws of rodents after tooth extraction. © 2012 International Journal of Experimental Pathology.

Effect of physical training on metabolic and bone profile in weaning rats

Introduction: The practice of moderate-intensity exercise can reduce the risk of infections and improve metabolic aspects of the person. Objective: To investigate the effects of aerobic physical training on endocrine and metabolic aspects, bone and immune systems. Methods: Twenty Wistar rats were divided in two groups: sedentary (SG) and trained group (TG). Training program consisted in swimming, 6 weeks, supporting a workload corresponding to 5% of body weight. At the end of the experiment, were performed counting total and differential leukocyte count and hematocrit. After training period, were analyzed glucose, total protein, triglycerides, cholesterol, liver and muscle samples for the determination of the levels of glycogen, and determination of the tibia length and bone area. All dependent variables were analyzed by one-way analysis of variance (ANOVA) and a significance level of P < 0.05 was used for all comparisons. Results: Hematocrit (%) analyzed showed a significant difference, with higher values ffor TG (54.63 ± 1.41) than for the SG (49.5 ± 1.65). The total leukocyte count was not significantly different, as there was no difference in the differential count. Total cholesterol showed significant decrease in TG (TG = 68.27 ± 13.71 mg/dL; SG = 94.44 ± 28.09), the total protein levels also showed significant reduction (TG = 7.3 ± 0.40 g/dL; SG = 7.74 ± 0.36 g/dL) glucose levels and triglyceride showed no significant differences. The bone length showed significant difference (TG = 40±0.14 mm; SG = 42.10 ± 0.12mm). Tibial area showed a lower value for TG (1.53 ± 0.12cm2) than for SG (1.67 ± 0.18cm2); however, the difference was not statistically significant. Conclusion: It can be concluded that aerobic exercise training is able to produce some unique physiological changes in young rats. There is also the need to prescribe exercises that meet the particular maturational stage of development.

Development and characterization of a new bio-nanocomposite (bio-NCP) for diagnosis and treatment of breast cancer

Breast cancer is a public health problem throughout the world. Moreover, breast cancer cells have a great affinity for hydroxyapatite, leading to a high occurrence of bone metastasis. In this work we developed a bio-nanocomposite (bio-NCP) in order to use such affinity in the diagnosis and treatment of breast cancer. The bio-NCP consists of magnetic nanoparticles of Mn and Zn ferrite inside a polymeric coating (chitosan) modified with nanocrystals of apatite. The materials were characterized with synchrotron X-ray Powder Diffraction (XPD), Time-of-Flight Neutron Powder Diffraction (NPD), Fourier Transformed Infra-red Spectroscopy (FTIR), Scanning Electron Microscopy (SEM) and magnetic measurement with a Physical Property Measurement System (PPMS). We obtained ferrite nanoparticles with a high inversion degree of the spinel structure regarding the Fe and Mn, but with all the Zn in the A site. The coating of such nanoparticles with chitosan had no notable effects to the ferrite microstructure. In addition, the polymeric surface can be easily modified with apatite nanocrystals since the hydration of the bio-NCP during synthesis can be controlled. The resulting bio-NCP presents a spherical shape with a narrow size distribution and high magnetic response at room temperature and is a very promising material for early diagnosis of breast cancer and its treatment. © 2013 Elsevier B.V.

Oral squamous carcinoma cells secrete RANKL directly supporting osteolytic bone loss

Objective: Local invasion of bone is a frequent complication of oral squamous cell carcinoma (OSCC). Development of these osteolytic lesions is mediated by osteoclasts. Receptor activation of NF-kappa B ligand (RANKL) signaling, counteracted by osteoprotegerin (OPG), regulates osteoclastogenesis. Previous studies in rodent models have demonstrated that inhibition of RANKL decreases tumor growth and lesions within bone. However, the contributory role of OSCC cells to this disease process has yet to be defined.Methods: RANKL expression was assessed in a panel of OSCC cell lines by qPCR, flow cytometry, and ELISA. Induction of osteoclastogenesis was assessed by co-culture with macrophages or with OSCC-derived conditioned medium. In an animal model of bone invasion, nude mice were injected intratibially with UMSCC-11B cells expressing a RANKL luciferase promoter to detect tumor-derived RANKL activity. Osteolytic lesions were analyzed by X-ray, micro-CT, and histological methods. RANKL expression was assessed in human OSCC tissues by immunohistochemistry.Results: We demonstrated that OSCCs express varied levels of all RANKL isoforms, both membrane-bound and soluble RANKL. Both co-culture and treatment with OSCC-conditioned media induced osteoclastogenesis. In mice, we demonstrated human RANKL promoter activity during bone invasion. Over the course of the experiment, animals suffered osteolytic lesions as RANKL-driven luciferase expression increased with time. After 8 weeks, human-derived RANKL was detected in areas of bone resorption by immunohistochemistry. Similar epithelial RANKL expression was detected in human OSCC tissues.Conclusion: These data demonstrate the ability of OSCCs to produce RANKL, directly altering the tumor microenvironment to increase osteoclastogenesis and mediate local bone invasion. (C) 2012 Elsevier Ltd. All rights reserved.

Relationship between chronological and bone ages and pubertal stage of breasts with bone biomarkers and bone mineral density in adolescents

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cellular behavior as a dynamic field for exploring bone bioengineering: A closer look at cell-biomaterial interface

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Bone Morphogenetic Proteins: Structure, biological function and therapeutic applications

Bone Morphogenetic Proteins (BMPs) are multifunctional secreted cytokines, which belong to the TGF-beta superfamily. These glycoproteins act as a disulfide-linked homo- or heterodimers, being potent regulators of bone and cartilage formation and repair, cell proliferation during embryonic development and bone homeostasis in the adult. BMPs are promising molecules for tissue engineering and bone therapy. The present review discusses this family of proteins, their structure and biological function, their therapeutic applications and drawbacks, their effects on mesenchymal stem cells differentiation, and the cell signaling pathways involved in this process. (C) 2014 Published by Elsevier Inc.

Association of matrix metalloproteinase inducer (EMMPRIN) with the expression of matrix metalloproteinases-1, -2 and -9 during periapical lesion development

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Silencing mitogen-activated protein kinase-activated protein kinase-2 arrests inflammatory bone loss

p38 mitogen-activated protein kinases (MAPKs) are critical for innate immune signaling and subsequent cytokine expression in periodontal inflammation and bone destruction. In fact, previous studies show that systemic p38 MAPK inhibitors block periodontal disease progression. However, development of p38 MAPK inhibitors with favorable toxicological profiles is difficult. Here, we report our findings regarding the contribution of the downstream p38 MAPK substrate, mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAPK-2), in immune response modulation in an experimental model of pathogen-derived lipopolysaccharide (LPS)-induced periodontal bone loss. To determine whether small interfering RNA (siRNA) technology has intraoral applications, we initially validated MK2 siRNA specificity. Then, gingival tissue surrounding maxillary molars of rats was injected with MK2 siRNA or scrambled siRNA at the palatal regions of bone loss. Intraoral tissues treated with MK2 siRNA had significantly less MK2 mRNA expression compared with scrambled siRNA-treated tissues. MK2 siRNA delivery arrested LPS-induced inflammatory bone loss, decreased inflammatory infiltrate, and decreased osteoclastogenesis. This proof-of-concept study suggests a novel target using an intraoral RNA interference strategy to control periodontal inflammation.

Fibroblast growth factor 17 and bone morphogenetic protein 15 enhance cumulus expansion and improve quality of in vitro-produced embryos in cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Surgical Treatment of Severe Frontal Bone Fracture

Craniofacial trauma can lead to several complications. The combined fractures of anterior and posterior walls of the frontal bone are almost always followed by lesions in nasofrontal orifices and disruption of nasofrontal ostia or ducts, a significant factor for the development of early and late complications after sinus fractures. This article reports a case of trauma patient, who underwent neurological evaluation and at first showed good general condition. Computed tomography noted fracture of the anterior and posterior walls of the frontal sinus and small foci of pneumocephalus in the cerebral cortex. The patient was monitored periodically and 9 days after trauma showed increased areas of pneumocephalus in prefrontal cortex, cerebrospinal fluid draining, and large dura mater lesion, with signs of necrosis and inflammation (meningitis). The necrotic tissues were removed, and dura mater was repaired through the approximation with resorbable wire polyglactin 910 5-0, oxidized cellulose application, and bonding with human fibrin sealant (fibrinogen, thrombin, and calcium chloride). Sinusectomy, frontal sinus, and nasofrontal duct obliteration with pedicled pericranium flap were performed. Tomographically, a reanatomization was noted in frontal region, and a 12-month follow-up showed no complication. The use of fibrin glue to repair dura mater lacerations, as well as the pedicle pericranium flap for frontal sinus and nasofrontal duct obliteration, is an efficient method for treating fractures of the frontal bone.

Bone mineral density in healthy female adolescents according to age, bone age and pubertal breast stage

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Clinical and surgical management of an aggressive cherubism treated with autogenous bone graft and calcitonin

Cherubism is a rare autosomal-dominant inherited syndrome and is usually self-limiting; it starts in early childhood and involutes by puberty. It is a benign fibroosseous disease, characterized by excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses. The purpose of this clinical report is to describe a rare and aggressive form of cherubism on an adult female patient that has been treated in our Bioscience Center for Special Health Care Needs-CEBAPE. The patient was firstly submitted to the surgical procedure with partial curettage of the lesion, and the cavity was filled with autogenous cancellous bone and bone marrow grafts. Furthermore, the support treatment used was the administration of salmon calcitonin by nasal spray during the first year after the preconized procedure. At 4-year followup, we confirmed the stomatognathic system improvement and esthetic rehabilitation, which led to a significant increase in the patient's quality of life.

Bone morphogenetic proteins: promising molecules for bone healing, bioengineering, and regenerative medicine

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Phenotypic, genetic and environmental parameters for traits related to femur bone integrity and body weight at 42 days of age in a broiler population

Intense selection among broilers, especially for performance and carcass traits, currently favors locomotion problems and bone resistance. Conducting studies relating to development and growth of bone tissue in broilers is necessary to minimize losses. Thus, genetic parameters were estimated for a broiler population's phenotypic traits such as BW at 42 d of age (BW42), chilled femur weight (CFW) and its yield (CFY), and femur measurements: calcium, DM, magnesium, phosphorus, and zinc content; breaking strength; rigidity; length; and thickness. Variance components were estimated through multitrait analyses using the restricted maximum likelihood method. The model included a fixed group effect (sex and hatch) and additive and residual genetic random effects. The heritability estimates we obtained ranged from 0.10 ± 0.05 to 0.50 ± 0.08 for chilled femur yield and BW42, respectively, and indicated that the traits can respond to the selection process, except for CFY, which presented low-magnitude heritability coefficients. Genetic correlation estimates between breaking strength, rigidity, and traits related to mineral content indicated that selection that aims to improve the breaking strength resistance of the femur is highly correlated with mineral content. Given the genetic correlation estimates between BW42 and minerals, it is suggested that in this population, selection for BW42 can be performed with greater intensity without affecting femoral integrity.