Bone Abstracts

Childhood and adolescence are critical periods for optimizing bone growth and mineral accrual. Bone strength is determined by bone size, geometry, quality, and mass – variables that are influenced by genetic factors, physical activity, nutrition, and pubertal hormones. Duchenne muscular dystrophy (DMD) and cerebral palsy (CP) are two chronic medical conditions of childhood associated with reduced mobility and increased rate of pathological fracture....

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...

Early-onset Paget’s disease of bone (ePDB), familial expansile osteolysis (FEO) and expansile skeletal hyperphosphatasia (ESH) are related syndromes caused by heterozygous tandem insertion duplication mutations within the signal peptide region of TNFRSF11a (encoding receptor activator of NFκB; RANK). Given that patients are always heterozygous for these mutations we have generated thirteen cell lines to investigate the molecular consequences of these mutations in...

Recessive osteogenesis imperfecta (OI) is caused by mutations in genes encoding proteins involved in post-translational interactions with type I collagen. A founder mutation in a new gene responsible for recessive OI has recently been reported in Bedouins from Israel and Saudi Arabia, who have a homozygous deletion of TMEM38B exon 4 and surrounding intronic sequence. TMEM38B encodes TRIC-B, an integral ER membrane monovalent cation channel involved in Ca...

Objectives: Bone development can be enhanced by exercise during growth, but not all types of exercise may be beneficial. Weight bearing and non-weight bearing sports have different effects on bone outcomes during adolescence. However, there is no longitudinal evidence comparing the effects of popular sports in the UK on bone acquisition in adolescent males.Methods: In the present study 116 adolescent males (13.1±0.1 years: 37 footballers, 37 swimmer...

Bone density (BMD) loss is a consequence of aromatase inhibitors (AI) treatment of breast cancer. B-ABLE cohort includes 391 postmenopausal women with early breast cancer starting AI therapy. Participants experienced a 1.98% (95% CI 1.54–2.42% P<0.0001) bone loss at lumbar spine (LS) and 1.24% (95% CI 0.81–1.67% P<0.0001) bone loss at femoral neck (FN) after 1 year on AI therapy and a 3.51% (95% CI 3.00–4.03% P<0.0001) bone...

Familial expansile osteolysis (FEO) is characterised by focal areas of increased bone turnover driven by bone-resorbing osteoclasts. The syndrome is caused by a heterozygous tandem insertion duplication mutation within the signal peptide region of TNFRSF11a (encoding receptor activator of NFκB; RANK). Our recent research has demonstrated that heterotrimeric receptor formation may hold the key to the disease phenotype. We have shown previously that, whilst homozygous overe...

Osteocytes may function as mechanotransducers by regulating local osteoclastogenesis. Reduced availability of oxygen, i.e. hypoxia could occur during disuse, bone development and fracture. Receptor activator of nuclear factor-κB ligand (RANKL) is an osteoblast/stromal cell derived essential factor for osteoclastogenesis. Hypoxia induced osteoclastogenesis via increased RANKL expression in osteoblasts was demonstrated. Hypoxic regulation of gene expression general...

Deficiency of Cyclophilin B (CyPB) causes recessively inherited Type IX osteogenesis imperfecta, a moderately severe to lethal bone dysplasia. CyPB, encoded by PPIB, is an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that catalyzes the rate-limiting step in collagen folding, and also functions as a component of the collagen prolyl 3-hydroxylation complex. We previously demonstrated in a Ppib−/− mouse model that CyPB PPIase activity r...

OPTN encodes a cytoplasmic protein optineurin which has been shown to play a role in autophagy. Recent GWAS studies have shown that variants within OPTN are associated with the risk of Paget’s disease of bone, a disease characterized by focal areas of increased bone turnover due to increased osteoclast activity, suggesting a possible role of OPTN in the regulation of bone metabolism.The aim of this study was to investigate the role of optineurin in ...