Absence of somatic SQSTM1 mutations in Paget's disease of bone.

Background: Paget's disease is a common focal bone disorder that appears to be caused by a combination of genetic and environmental factors. Mutations in the SQSTM1 gene are found in about one third of families with Paget's disease and 8% of sporadic cases. Other potential loci linked to the disease have also been identified, and a number of environmental factors have been suggested to be involved in the disease.

Failure to detect measles virus ribonucleic acid in bone cells from patients with Paget's disease.

Background: Paget's disease is a condition of focal accelerated bone turnover. Electron-microscopy investigations of osteoclasts from pagetic lesions have identified nuclear inclusion bodies that have a similar appearance to viral nucleocapsid particles. Subsequently, RNA from several paramyxoviruses has been detected in pagetic tissue, and it was suggested that these viruses, in particular measles, might play a role in the etiology of Paget's disease.

Imatinib promotes osteoblast differentiation by inhibiting PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent mechanisms.

Unlabelled: Several lines of evidence suggest that imatinib may affect skeletal tissue. We show that inhibition by imatinib of PDGFR signaling in osteoblasts activates osteoblast differentiation and inhibits osteoblast proliferation and that imatinib inhibits osteoclastogenesis by both stromal cell-dependent and direct effects on osteoclast precursors.

Introduction: Imatinib mesylate, an orally active inhibitor of the c-abl, c-kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is in clinical use for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal cell tumors.

Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget's disease of bone.

Unlabelled: Paget's disease is a focal condition of bone. To study changes in cells within pagetic lesions, we cultured osteoblasts and stromal cells from 22 patients and compared gene expression in these cells to cells from healthy bone. We identified several differentially regulated genes, and we suggest that these changes could lead to the formation of the lesions.

Lactoferrin potently inhibits osteoblast apoptosis, via an LRP1-independent pathway.

Lactoferrin induces osteoblast proliferation in vitro and is anabolic to bone in vivo. We recently reported that the low-density lipoprotein-receptor-related protein 1 (LRP1), a multifunctional member of the LDL receptor family, transduces the mitogenic signal activated by lactoferrin. Here we investigate the effects of lactoferrin on osteoblast survival.

Deletion of aspartate 182 in OPG causes juvenile Paget's disease by impairing both protein secretion and binding to RANKL.

Unlabelled: Mutations in the OPG gene cause idiopathic hyperphosphatasia. We characterized the effects of one such mutation and found that the mutant OPG is poorly secreted and has reduced biological activity compared with the wildtype protein. Therefore, correct structure and cellular processing of OPG is essential for normal bone remodeling.

Parallel phosphatidylinositol-3 kinase and p42/44 mitogen-activated protein kinase signaling pathways subserve the mitogenic and antiapoptotic actions of insulin-like growth factor I in osteoblastic cells.

IGF-I is an endocrine and paracrine regulator of skeletal homeostasis, principally by virtue of its anabolic effects on osteoblastic cells. In the current study, we examined the intracellular signaling pathways by which IGF-I promotes proliferation and survival in SaOS-2 human osteoblastic cells. Inhibition of each of the phosphatidylinositol-3 kinase (PI-3 kinase), p42/44 MAPK, and p70s6 kinase pathways partially inhibited the ability of IGF-I to stimulate osteoblast proliferation and survival.

The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase.

The naturally occurring phospholipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) have recently emerged as bioactive compounds that exert mitogenic effects in many cell types, including osteoblasts. In the current study, we examined the ability of each of these compounds to influence osteoblast survival. Using terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate nick-end labeling and DNA fragmentation assays, we found that both LPA and S1P dose-dependently inhibited (by at least 50% and 40%, respectively) the apoptosis induced by serum withdrawal in cultures of primary calvarial rat osteoblasts and SaOS-2 cells.