19 research outputs found
P2 receptors in macrophage fusion and osteoclast formation
Cells of the mononuclear phagocyte lineage fuse to form multinucleated giant cells and osteoclasts. Several lines of evidence suggest that P2 receptors, in particular P2X7, are involved in this process, although P2X7 is not absolutely required for fusion because P2X7-null mice form multinucleated osteoclasts. Extracellular ATP may be an important regulator of macrophage fusion
The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase
Tumour metastasis is a complex process involving reciprocal interplay
between cancer cells and host stroma at both primary and secondary
sites, and is strongly influenced by microenvironmental
factors such as hypoxia. Tumour-secreted proteins play a crucial role
in these interactions and present strategic therapeutic potential.
Metastasis of breast cancer to the bone affects approximately 85%
of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed,
lead to debilitating skeletal complications and increased patient morbidity
and mortality. The molecular interactions governing the
early events of osteolytic lesion formation are currently unclear.
Here we show hypoxia to be specifically associated with bone relapse
in patients with oestrogen-receptor negative breast cancer. Global
quantitative analysis of the hypoxic secretome identified lysyl oxidase
(LOX) as significantly associated with bone-tropism and relapse.
High expression of LOX in primary breast tumours or systemic delivery
of LOX leads to osteolytic lesion formation whereas silencing or
inhibition of LOX activity abrogates tumour-driven osteolytic lesion
formation. We identify LOX as a novel regulator of NFATc1-driven
osteoclastogenesis,independent of RANK ligand, which disrupts normal
bone homeostasisleading to the formation of focal pre-metastatic
lesions. We show that these lesions subsequently provide a platform
for circulating tumour cells to colonize and form bone metastases.
Our study identifies a novel mechanism of regulation of bone homeostasis
and metastasis, opening up opportunities for novel therapeutic
intervention with important clinical implications
Molecular and functional properties of P2X receptors—recent progress and persisting challenges
A thermosensitive chitosan/corn starch/β-glycerol phosphate hydrogel containing TGF-β1 promotes differentiation of MSCs into chondrocyte-like cells
A La protein requirement for efficient pre-tRNA folding
The La protein protects the 3′ ends of many nascent small RNAs from exonucleases. Here we report that La is required for efficient folding of certain pre-tRNAs. A mutation in pre-tRNA(Arg)(CCG) causes yeast cells to be cold-sensitive and to require the La protein Lhp1p for efficient growth. When the mutant cells are grown at low temperature, or when Lhp1p is depleted, mature tRNA(Arg)(CCG) is not efficiently aminoacylated. The mutation causes the anticodon stem of pre-tRNA(Arg)(CCG) to misfold into an alternative helix in vitro. Intragenic suppressor mutations that disrupt the misfolded helix or strengthen the correct helix alleviate the requirement for Lhp1p, providing evidence that the anticodon stem misfolds in vivo. Chemical and enzymatic footprinting experiments suggest a model in which Lhp1p stabilizes the correctly folded stem. Lhp1p is also required for efficient aminoacylation of two wild-type tRNAs when yeast are grown at low temperature. These experiments reveal that pre-tRNAs can require protein assistance for efficient folding in vivo
Dorsal Plating of Unstable Distal Radius Fractures Using a Bio-Absorbable Plating System and Bone Substitute
Expression, signaling, and function of P2X7 receptors in bone
Nucleotides released from cells in response to mechanical stimulation or injury may serve as paracrine regulators of bone cell function. Extracellular nucleotides bind to multiple subtypes of P2 receptors on osteoblasts (the cells responsible for bone formation) and osteoclasts (cells with the unique ability to resorb mineralized tissues). Both cell lineages express the P2X7 receptor subtype. The skeletal phenotype of mice with targeted disruption of P2rx7 points to interesting roles for this receptor in the regulation of bone formation and resorption, as well as the response of the skeleton to mechanical stimulation. This paper reviews recent work on the expression of P2X7 receptors in bone, their associated signal transduction mechanisms and roles in regulating bone formation and resorption. Areas for future research in this field are also discussed