Abstract
Bone resorption mediated by osteoclasts is a prominent feature of many chronic inflammatory diseases. Osteoclast differentiation and activation appear to be dependent upon soluble factors such as IL-1 and TNF-α (tumor necrosis factor-α) that induce the cytokine RANKL (also called TRANCE); RANKL, in turn, activates NF-κB (nuclear factor-κB), which drives osteoclast differentiation. Investigators have developed a peptide, NBD, that blocks TNF-α-induced NF-κB activation. They have shown that this inhibitory peptide inhibits RANKL-induced osteoclastogenesis in vitro and in vivo, but does not affect osteoblast differentiation in vitro. Moreover, in a mouse model of LPS-induced pathologic bone resorption, intraperitoneal injection of the NBD peptide blocked NF-κB activation in osteoclast precursors. In collagen-induced arthritis in mice, a model for rheumatoid arthritis in man, NBD-treated animals had delayed disease onset, lower incidence of disease, and reduced disease severity compared to control animals. Administration of NBD appears to be a promising approach to therapy of chronic inflammatory conditions associated with bone destruction.
Jimi E, Aoki K, Saito H, D-Acquisto, May MJ, Nakamura I, Sudo T, Kojima T, Okamoto F, Fukushima H, Okabe K, Ohya K, Ghosh S: Selective inhibition of NF-κB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat Med 10:617–624, 2004
Most metastatic spread of solid tumors occurs via the lymphatic system, but little is known about the formation of tumor-associated lymphatic vessels. To investigate this, Finnish investigators injected Lewis lung carcinoma and B16 melanoma cells into syngeneic C57BL mice that had been transplanted with a green fluorescent protein (GFP)-expressing bone marrow and showed that GFP-positive lymphatic endothelium precursor cells did not contribute to the peri-tumoral lymphatic network. By microlymphography, these investigators demonstrated that tumor-induced lymphatic vessels originated from pre-existing lymphatic networks; most lymphatic vessels were within 1 mm of the tumor margin and these vessels rarely penetrated more than 2 mm into the tumor. In VEGF-C± mice with faulty lymphangiogenesis, metastasis of tumors to regional lymph nodes was suppressed; however, lung metastasis was not affected. Thus, lymphatic metastasis of solid tumors appears to occur via newly formed tumor-associated lymphatic vessels.
He Y, Rajantic M, Makinen T, Karkkainen MJ, Haiko P, Salven P, Alitalo K: Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 64:3737–3740, 2004
In response to microbial invasion and tissue injury, neutrophils undergo rapid changes in morphology, behavior, and function. However, the mechanisms of gene expression regulation that allow this rapid response are poorly understood. A group of scientists in Utah recently showed that neutrophils have specialized translational control mechanisms that allow rapid synthesis and release of inflammatory mediators. Platelet-activating factor stimulated the synthesis of IL-6 receptor α subunit, a key inflammatory modulator, not by enhancing transcription of the gene, but by triggering translocation of pre-existing mRNA from monosomes to polysomes. Furthermore, this process was controlled by the intracellular kinase mTOR (mammalian target of rapamycin). This newly discovered pathway for neutrophil activation may be a promising target for therapeutic modulation of the inflammatory milieu.
Lindemann SW, Yost CC, Denis MM, McIntyre TM, Weyrich AS, Zimmerman GA: Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs. Proc Natl Acad Sci (USA) 101:7076–7081, 2004
Wet scanning electron microscopy (wet SEM) utilizes a sealed specimen capsule to allow high-resolution imaging of wet biological samples by collecting backscattered electrons. To demonstrate this system, investigators treated rats with D-limonene to induce hyaline droplet formation in the kidneys, perfused the animals with glutaraldehye-formaldehyde fixative at necropsy, sectioned the kidneys into 0.5-mm slices with a vibratome, stained the sections with uranyl acetate, and examined them by wet SEM. Using this technique, structures within a few microns of the tissue surface were visualized with excellent resolution, contrast, and magnification. This technique allows examination of tissues within an hour of removal, thus offering a rapid alternative to conventional light microscopy.
Nyska A, Cummings CA, Vainshtein A, Nadler J, Ezov N, Grunfeld Y, Gileadi O, Behar V: Electron microscopy of wet tissues: a case study in renal pathology. Toxicol Pathol 32:357–363, 2004
There are more than 400 breeds of dog with distinctive morphologic features and disease susceptibilities. Using microsatellite typing, investigators have been able to establish a genetic classification of dog breeds. Their studies have revealed a variety of interesting relationships. The wolf is the direct ancestor of the domestic dog. Most dog breeds are genetically isolated from other breeds and have unique genetic signatures that can be used for breed identification. There are at least four distinct breed groupings. There is a group of breeds, including the Basenji, Lhasa Apso, Pekingese, Akita, and Siberian Husky breeds, that represents dogs of ancient Asian and African origin. Most other breeds appear to have been recently derived from a shared European stock. This cluster of breeds can be separated into three sub-populations with shared genetic features: Mastiff-like breeds, herding breeds, and hunting breeds.
Parker HG, Kim LV, Sutter NB, Carlson S, Lorentzen TD, Malek TB, Johnson GS, DeFrance HB, Ostrander EA, Kruglyak L: Genetic structure of the purebred domestic dog. Science 304:1160–1164, 2004
Hemangiosarcoma is a common malignancy of dogs that arises from vascular endothelial cells. The tumor is aggressive and treatment is often unsuccessful. In an attempt to learn more about the nature of this tumor, veterinary scientists established and characterized eight independent cell lines from canine hemangiosarcomas. The cell lines have the characteristics of primitive endothelial cells. They express endothelial cell antigens including CD31, CD146, CD105, and CD51/CD61, although some cell lines do not express vonWillebrand factor. The cell lines have unstable karyotypes, show anchorage-independent growth, and invade a Matrigel matrix. However, the cell lines require endothelial growth factors, show contact inhibition, and can be induced to form tubular blood vessel–like structures by inactivation of calcium-dependent signaling pathways. Hemangiosarcoma cell lines express CD117 (c-Kit) the receptor for stem-cell factor, a marker of hematopoietic stem cells. Interestingly, c-Kit does not appear to be expressed in benign lesions of the vascular endothelium. Thus, CD117 may be useful for differentiating benign from malignant vascular lesions.
Fosmire SP, Dickerson EB, Scott AM, Bianco SR, Pettengill MJ, Meylemans H, Padilla M, Frazer-Abel AA, Akhtar N, Getzy DM, Wojcieszyn J, Breen M, Helfand SC, Modiano JF: Canine malignant hemangiosarcoma as a model of primitive angiogenic endothelium. Lab Invest 84:562–572, 2004