Bone Formation Under Sinus Using Venous Coagulum

Authors

Kathleen A Beaudry, DMD, MS, Nicolaas C Geurs, DDS, MS, Jack E Lemons, PhD, Michael S Reddy, DMD, DMSc

Abstract

Introduction: Insufficient bone height is a common obstacle to placing dental implants in the posterior maxilla. Sinus grafts have been shown to be a highly predictable way to increase bone height in the posterior maxilla. This case series illustrates a technique using venous coagulum and simultaneous implant placement under the elevated sinus. Bone formation is demonstrated clinically, radiographically, and histologically. To our knowledge, this is the first report of histomorphometric results and micro computed tomography using this technique. Case Presentation: A total of 5 sinus elevations with simultaneous placement of 2 dental implants were performed with venous blood coagulum as the sole filling biomaterial. At the time of uncovery, following 8-9 months healing, biopsies were harvested from the lateral wall of the maxilla. This article illustrates bone formation under 5 elevated sinuses, with simultaneous placement of dental implants, using venous coagulum as the sole filling material. Results show significant gains in bone height adjacent to the implant. MicroCT shows well-structured trabecular bone. Histomorphometry of biopsies show 38-74% vital bone. Conclusions: This case series illustrates that bone grafting materials in the subsinus cavity are not required for successful placement of implants. Utilization of ones own blood as filling material removes any objections to grafting including religious, ethical, or fear of disease transmission. Venous coagulum is a simple, inexpensive biomaterial and its systematic use during a sinus lift may be a relevant option, ultimately leading to increased access to implant treatment options for patients.

Link to Article

http://dx.doi.org/10.1902/cap.2013.120120

Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice

Authors

Karen A Dunphy, Anneke C Blackburn, Haoheng Yan, Lauren R O'Connell, D Joseph Jerry

Abstract

INTRODUCTION: Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. METHODS: Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues. RESULTS: Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors. CONCLUSION: Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.

Link to Article

http://dx.doi.org/10.1186/bcr2094

Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

Authors

Jesmond Dalli, Angelo P. Consalvo, Vicki Ray, Clara Di Filippo, Michele D’Amico, Nozer Mehta and Mauro Perretti

Abstract

Endogenous mechanisms regulating the host response during inflammation resolution are critical in ensuring disposal of noxious stimuli and return to homeostasis. In this article, we engineered novel Annexin A1 (AnxA1)–based peptides, AnxA12–50, that displayed specific binding to the AnxA1 receptor (formyl peptide receptor 2/Lipoxin A4 receptor [FPR2/ALX]; IC50 ∼4 nM). Intravenous administration of AnxA12–50 markedly reduced (>60%) leukocyte adhesion to postcapillary venules in wild type and Fpr1−/−, but not Fpr2/Alx−/−, mice. Generation of a metabolically stable form of this peptide (CR-AnxA12–50), engineered by substituting a cleavage site shared by human proteinase 3 and neutrophil elastase, yielded an agonist that was resistant to neutrophil-mediated cleavage and displayed enhanced proresolving actions: accelerated resolution of self-limited inflammation and enhanced macrophage efferocytosis after sterile injury, when compared with AnxA12–50. These actions were retained with human primary leukocytes where CR-AnxA12–50 decreased neutrophil–endothelial interactions (∼25–45%), and stimulated neutrophil apoptosis and macrophage efferocytosis (∼45%). In murine cardiac ischemia/reperfusion injury, CR-AnxA12–50 elicited tissue-protective actions reducing infarct size (∼60%) and incidence of 24-h death. These results identify AnxA12–50 and CR-AnxA12–50 as FPR2/ALX agonists that harness the proresolving actions of AnxA1, and thus may represent therapeutic tools for treatment of inflammatory conditions.

Link to Article

http://dx.doi.org/10.4049/immunol.1203000

Mice Lacking Pten in Osteoblasts Have Improved Intramembranous and Late Endochondral Fracture Healing

Authors

Travis A. Burgers, Martin F. Hoffmann, Caitlyn J. Collins, Juraj Zahatnansky, Martin A. Alvarado, Michael R. Morris, Debra L. Sietsema, James J. Mason, Clifford B. Jones, Heidi L. Ploeg, Bart O. Williams

Abstract

The failure of an osseous fracture to heal (development of a non-union) is a common and debilitating clinical problem. Mice lacking the tumor suppressor Pten in osteoblasts have dramatic and progressive increases in bone volume and density throughout life. Since fracture healing is a recapitulation of bone development, we investigated the process of fracture healing in mice lacking Pten in osteoblasts (Ocn-cretg/+;Ptenflox/flox). Mid-diaphyseal femoral fractures induced in wild-type and Ocn-cretg/+;Ptenflox/flox mice were studied via micro-computed tomography (µCT) scans, biomechanical testing, histological and histomorphometric analysis, and protein expression analysis. Ocn-cretg/+;Ptenflox/flox mice had significantly stiffer and stronger intact bones relative to controls in all cohorts. They also had significantly stiffer healing bones at day 28 post-fracture (PF) and significantly stronger healing bones at days 14, 21, and 28 PF. At day 7 PF, the proximal and distal ends of the Pten mutant calluses were more ossified. By day 28 PF, Pten mutants had larger and more mineralized calluses. Pten mutants had improved intramembranous bone formation during healing originating from the periosteum. They also had improved endochondral bone formation later in the healing process, after mature osteoblasts are present in the callus. Our results indicate that the inhibition of Pten can improve fracture healing and that the local or short-term use of commercially available Pten-inhibiting agents may have clinical application for enhancing fracture healing.

Link to Article

http://dx.doi.org/10.1371/journal.pone.0063857

Roquin Promotes Constitutive mRNA Decay via a Conserved Class of Stem-Loop Recognition Motifs

Authors

Kathrin Leppek, Johanna Schott, Sonja Reitter, Fabian Poetz, Ming C. Hammond, Georg Stoecklin

Abstract

Tumor necrosis factor-α (TNF-α) is the most potent proinflammatory cytokine in mammals. The degradation of TNF-α mRNA is critical for restricting TNF-α synthesis and involves a constitutive decay element (CDE) in the 3′ UTR of the mRNA. Here, we demonstrate that the CDE folds into an RNA stem-loop motif that is specifically recognized by Roquin and Roquin2. Binding of Roquin initiates degradation of TNF-α mRNA and limits TNF-α production in macrophages. Roquin proteins promote mRNA degradation by recruiting the Ccr4-Caf1-Not deadenylase complex. CDE sequences are highly conserved and are found in more than 50 vertebrate mRNAs, many of which encode regulators of development and inflammation. In macrophages, CDE-containing mRNAs were identified as the primary targets of Roquin on a transcriptome-wide scale. Thus, Roquin proteins act broadly as mediators of mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs.

Link to Article

http://dx.doi.org/10.1016/j.cell.2013.04.016

Liver X receptor activation inhibits osteoclastogenesis by suppressing NF-κB activity and c-Fos induction and prevents inflammatory bone loss in mice

Authors

Hyun-Ju Kim, Kyung-Ae Yoon, Hye-Jin Yoon, Jung Min Hong, Min-Jung Lee, In-Kyu Lee and Shin-Yoon Kim

Abstract

LXRs are nuclear receptors that function as important regulators of lipid homeostasis and inflammatory responses. LXR activation has been shown to suppress RANKL-induced osteoclast differentiation, but its underlying mechanisms and its influence on inflammatory bone destruction remain unclear. In this study, we report that the LXR agonists T0901317 and GW3965 inhibit osteoclastogenesis from primary BMMs in a dose-dependent manner. LXR activation suppressed RANKL-induced transcriptional activity of NF-κB without affecting IκBα degradation and the phosphorylation of p38. LXR agonists significantly suppressed RANKL-induced expression of c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. The activation of LXRs also inhibited RANKL-mediated AP-1 transcriptional activity. Furthermore, LXR activation attenuated PPARγ ligand-induced c-Fos expression, and LXR suppressed AP-1 promoter activity by PPARγ. The inhibitory effect of LXR activation on osteoclastogenesis was reversed by overexpression of c-Fos, suggesting that c-Fos is a downstream target of the antiosteoclastogenic action of LXRs. In addition to osteoclast differentiation, LXR activation accelerated apoptosis in mature osteoclasts by the induction of caspase-3 and -9 activity and Bim expression. Consistent with the in vitro effects we observed, the administration of a LXR agonist protected from bone loss induced by LPS in vivo. Together, our data provide evidence that LXRs may have potential as therapeutic targets for bone resorption-associated diseases.

Link to Article

http://dx.doi.org/10.1189/jlb.1112601