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Treatment with anti-TNF-[alpha] MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-[alpha] signaling in epithelial cells is involved in the development of CAC. To investigate this, we studied the effects of anti-TNF-[alpha] MAb in an animal model of CAC by administration of azoxymethane (AOM) followed by sequential dextran sodium sulfate (DSS) ingestion. We observed that the NF-[kappa]B pathway is activated in colonic epithelia from DSS-administered mice in association with upregulation of TNFR2 rather than TNFR1. Immunoblot analysis also revealed that the TNFR2 upregulation accompanied by the NF-[kappa]B activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-[kappa]B activity in the epithelial cells is significantly suppressed by the treatment of MP6-XT22, an anti-TNF-[alpha] MAb. Despite inability to reduce the severity of colitis, sequential administration of MP6-XT22 reduced the numbers and size of tumors in association with the NF-[kappa]B inactivation. Taken together, present studies suggest that the TNFR2 signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis and imply that the maintenance therapy with anti-TNF-[alpha] MAb may prevent the development of CAC in patients with long-standing IBD. tumor necrosis factor-[alpha]; colitis-associated cancer; intestinal epithelial cells; carcinogenesis; TNFR2

Author(s): Kojiro Sato [1, 11]; Ayako Suematsu [1, 11]; Tomoki Nakashima [1]; Sayaka Takemoto-Kimura [2]; Kazuhiro Aoki [3]; Yasuyuki Morishita [4]; Hiroshi Asahara [5]; Keiichi Ohya [3]; Akira Yamaguchi [6]; [...]

Activating receptor activator of NF-[kappa]B (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies [...]

Bone destruction is a pathological hallmark of several chronic inflammatory diseases, including rheumatoid arthritis and periodontitis. Inflammation-induced bone loss of this sort results from elevated numbers of bone-resorbing osteoclasts. Gene targeting studies have shown that the transcription factor nuclear factor-[kappa]B (NF-[kappa]B) has a crucial role in osteoclast differentiation, and blocking NF-[kappa]B is a potential strategy for preventing inflammatory bone resorption. We tested this approach using a cell-permeable peptide inhibitor of the I[kappa]B-kinase complex, a crucial component of signal transduction pathways to NF-[kappa]B. The peptide inhibited RANKL-stimulated NF-[kappa]B activation and osteoclastogenesis both in vitro and in vivo. In addition, this peptide significantly reduced the severity of collagen-induced arthritis in mice by reducing levels of tumor necrosis factor-[alpha] and interleukin-1[beta], abrogating joint swelling and reducing destruction of bone and cartilage. Therefore, selective inhibition of NF-[kappa]B activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption., Author(s): Eijiro Jimi [1, 5]; Kazuhiro Aoki [2]; Hiroaki Saito [2]; Fulvio D'Acquisto [1]; Michael J May [1, 6]; Ichiro Nakamura [3]; Testuo Sudo [4]; Takefumi Kojima [2]; Fujio Okamoto [...]

The purpose of this study was to evaluate a thin gelatin hydrogel membrane containing p-tricalcium phosphate (G-TCP) for use in guided bone regeneration, a technique that we developed. G-TCP membranes were fabricated from gelatin and β-TCP powder, freeze-dried, and cross-linked by heating. The resulting G-TCP membranes were as thin as collagen membranes, with high mechanical integrity. Proliferation and differentiation of rat bone marrow stromal cells (BMSCs) on G-TCP and collagen membranes were examined. On both membranes, BMSCs proliferated well and expressed alkaline phosphatase. However, more bone-like mineralized tissue formed on G-TCP membranes than on collagen membranes at 4 weeks. The effects of G-TCP and collagen membranes on bone regeneration in rat parietal bone defects were histologically examined. Bone bridges with mature uniform bone were observed under G-TCP membranes as early as 2 weeks. These results indicate that G-TCP is a GBR membrane that is comparable or superior to collagen membrane. [ABSTRACT FROM AUTHOR]

Purpose The aim of the present study was to evaluate the feasibility of a gelatin hydrogel system to enhance recombinant human fibroblast growth factor-2 (rhFGF-2)–induced osteogenic effects during rat mandibular distraction. Materials and Methods Mandibular distraction was performed in 28 male Wistar rats. Then, the rats were divided into 5 groups in which the designated gel mix was inserted into the distracted area: group 1, rhFGF-2 alone (n = 5); group 2, collagen alone (n = 6); group 3, collagen incorporating rhFGF-2 (n = 6); group 4, gelatin hydrogel alone (n = 5); and group 5, gelatin hydrogel incorporating rhFGF-2 (n = 6). The mandibles were excised 29 days after surgery and the newly formed bone was analyzed radiologically and histologically. The experimental groups were compared using the Fisher post hoc test (95% statistical significance threshold; P < .05). Results Peripheral quantitative computed tomographic analysis, von Kossa staining, and calcein staining showed that using gelatin hydrogel with rhFGF-2 (group 5) significantly increased cortical bone mineral density, the domain area of hard tissue, the domain area of cortical bone area, total bone mineral content, cortical bone mineral content, the von Kossa–stained area, and the calcein-stained area compared with the collagen carrier (group 3). Group 5 also had a significantly larger number of cells positive for tartrate-resistant acid phosphatase compared with group 3 and radiopaque areas were observed more frequently. Conclusions The present findings suggest that gelatin hydrogel is a feasible delivery system for rhFGF-2, and when used together perform better in regard to hard tissue healing and treatment time after surgery. [ABSTRACT FROM AUTHOR]

ABSTRACT p130Cas, Crk-associated substrate (Cas), is an adaptor/scaffold protein that plays a central role in actin cytoskeletal reorganization. We previously reported that p130Cas is not tyrosine-phosphorylated in osteoclasts derived from Src-deficient mice, which are congenitally osteopetrotic, suggesting that p130Cas serves as a downstream molecule of c-Src and is involved in osteoclastic bone resorption. However, the physiological role of p130Cas in osteoclasts has not yet been confirmed because the p130Cas-deficient mice displayed embryonic lethality. Osteoclast-specific p130Cas conditional knockout (p130CasΔOCL-) mice exhibit a high bone mass phenotype caused by defect in multinucleation and cytoskeleton organization causing bone resorption deficiency. Bone marrow cells from p130CasΔOCL- mice were able to differentiate into osteoclasts and wild-type cells in vitro. However, osteoclasts from p130CasΔOCL- mice failed to form actin rings and resorb pits on dentine slices. Although the initial events of osteoclast attachment, such as β3-integrin or Src phosphorylation, were intact, the Rac1 activity that organizes the actin cytoskeleton was reduced, and its distribution was disrupted in p130CasΔOCL- osteoclasts. Dedicator of cytokinesis 5 (Dock5), a Rho family guanine nucleotide exchanger, failed to associate with Src or Pyk2 in osteoclasts in the absence of p130Cas. These results strongly indicate that p130Cas plays pivotal roles in osteoclastic bone resorption. © 2013 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Mechanical unloading, such as in a microgravity environment in space or during bed rest (for patients who require prolonged bed rest), leads to a decrease in bone mass because of the suppression of bone formation and the stimulation of bone resorption. To address the challenges presented by a prolonged stay in space and the forthcoming era of a super-aged society, it will be important to prevent the bone loss caused by prolonged mechanical unloading. Nuclear factor κB (NF-κB) transcription factors are activated by mechanical loading and inflammatory cytokines. Our objective was to elucidate the role of NF-κB pathways in bone loss that are caused by mechanical unloading. Eight-week-old wild-type (WT) and NF-κB1-deficient mice were randomly assigned to a control or mechanically unloaded with tail suspension group. After 2 weeks, a radiographic analysis indicated a decrease in bone mass in the tibias and femurs of the unloaded WT mice but not in the NF-κB1-deficient mice. An NF-κB1 deficiency suppressed the unloading-induced reduction in bone formation by maintaining the proportion and/or potential of osteoprogenitors or immature osteoblasts, and by suppression of bone resorption through the inhibition of intracellular signaling through the receptor activator of NF-κB ligand (RANKL) in osteoclast precursors. Thus, NF-κB1 is involved in two aspects of rapid reduction in bone mass that are induced by disuse osteoporosis in space or bed rest. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Because high doses of bone morphogenetic proteins (BMPs) are required to achieve a certain level of bone regeneration in primates, thereby causing side effects such as inflammation, combination therapies using BMPs along with agents that can reduce the required amount of BMPs have been developed. Recently, we found that subcutaneous injections of W9 peptide (W9), which has been established as a tumor necrosis factor (TNF)-α and receptor activator of nuclear factor-κB ligand (RANKL) antagonist, promoted BMP-induced ectopic bone formation. Since TNF-α is known to reduce bone formation, we investigated the stimulatory mechanism of W9 on bone formation by using TNF-α-deficient, TNF type 1 receptor (TNFR1)-deficient, and wild-type (WT) mice. Methods: Collagen discs containing either BMP-2 (1μg) alone or BMP-2 (1μg) with W9 (0.56mg) (BMP-2+W9) were implanted into the back muscles of 5-week-old male mice. The animals were sacrificed on day 12 after implantation. Radiographic and histomorphometric analyses were performed on the dissected ectopic bones. Results: A significant increase in ectopic bone was observed in the BMP-2+W9 group compared to the BMP-2 group in WT mice. Bone histomorphometric technique revealed a significant increase of osteoblast surface and mineralized bone indices in the BMP-2+W9 group compared to the BMP-2 group in WT mice. Interestingly, W9 also increased the bone mineral content of ectopic bone induced by BMP-2 in both TNF-α deficient and TNFR1-deficient mice, to the same extent as in WT mice. Conclusion: Our data suggest that W9 promotes bone formation by a mechanism other than antagonism of TNF-α action. [Copyright &y& Elsevier]