Bone Abstracts

see PP493....

Abstract: Paget’s disease of bone (PDB) is characterised by focal lesions of local bone turnover driven by overactive osteoclasts, which often contain nuclear and cytoplasmic inclusion bodies. Mutations affecting the sequestosome-1 (SQSTM1) ubiquitin-associated (UBA) domain have been identified in individuals with PDB. SQSTM1, also known as p62, is a ubiquitously-expressed scaffold protein of 62 kDa that functions in multiple signalling pathways important for cell surviva...

Osteoclasts secrete acid and cathepsin K to dissolve the mineral and digest the organic matrix of bone, cartilage and dentine. The secretions are by necessity destructive and potentially harmful to the cell itself and are therefore trafficked through the cell in membrane bound vesicles. Secretion takes place over a specialised membrane compartment, the ruffled border, which is only present in resorbing osteoclasts. The ruffled border membrane and the vesicles in its vicinity h...

Paget’s disease of Bone (PDB) is caused by mutations in the gene encoding Sequestosome-1 (Q17STM1 or p62) that affect the C-terminal Ubiquitin-Associated (UBA) domain. A second isoform of Q17STM1 exists (referred to hereafter as 55kDa-Q17STM1), which lacks the N-terminal Phox and Bem1 (PB1) domain and has previously been reported to be ~45x more abundant than Q17STM1/p62 in osteoclasts. Mutations in the UBA domain will also occur in this isoform. Several of the UBA mutati...

Osteoclasts are the only cell type capable of resorption of mineralised matrix such as bone or dentine. Resorbing osteoclasts form distinct membrane domains: the functional secretory, the basolateral and the ruffled border (RB) domains. The RB allows acidification of the resorption lacuna, exocytosis of osteolytic enzymes and uptake of degraded bone material, processes that require directed vesicular transport. Few studies have tried to classify the vesicles near the RB into s...

The Rab family GTPases Rab27a and Rab27b play an important role in the trafficking of lysosome-related organelles in specialised cells, such as melanocytes. Since secretory lysosomes, also considered a lysosome-related organelle, are important for osteoclast and osteoblast function, we hypothesised that Rab27 plays a role in bone physiology. In support of this, a recent study demonstrated impaired transport of RANK ligand to the plasma membrane in osteoblasts from mice lacking...

Osteoclast-poor autosomal recessive osteopetrosis is characterised by susceptibility to fracture despite high bone mineral density as a consequence of an absence of osteoclasts. One of the 12 receptor activator of NF-κB (RANK) mutations associated with this condition is a frameshift mutation encoding a protein that is truncated within the extracellular, N-terminal domain (R110Pfs). We investigated the effect of this mutation on osteoclast formation, receptor localisation ...

Shwachman Diamond syndrome (SDS; MIM 260400) is a monogenic, autosomal recessive, pancreatic condition often accompanied by low bone mass and fracture. In SDS, as in cystic fibrosis, a low bone mass may be secondary to poor nutrition or chronic low-grade infection, but it has also been suggested there may be a primary bone phenotype. Paradoxically, recent studies in cell lines and in a mouse knockout for the SBDS gene, have suggested changes in important osteoclast gr...

Twelve different mutations in TNFRSF11A (encoding the RANK receptor) have been associated with osteoclast-poor autosomal recessive osteopetrosis in patients. Two truncated RANK proteins resulting from substitution mutations (W434X and G280X), identified in two infants, cause loss of the intracellular oligomerisation motif and in the case of the G280X mutation the TRAF6 binding domain. A third mutation was identified in a 10-year-old patient and is a frameshift mutatio...

The autophagy protein LC3 is necessary for bone resorption by osteoclasts, although it has been suggested that this may be through a novel, autophagy-independent process, by promoting lysosomal fusion at the ruffled border (RB). This process would be analogous to LC3-associated phagocytosis (LAP), in which LC3 is acquired by phagosomes through an autophagy-independent process, and controls phagosome maturation by promoting fusion with lysosomes. We have investigated this possi...